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4. Combinatorics of generalized parking-function polytopes

Author

Bayer, Margaret M., Borgwardt, Steffen, Chambers, Teressa, Daugherty, Spencer, Dawkins, Aleyah, Deligeorgaki, Danai, Liao, Hsin-Chieh, McAllister, Tyrrell, Morrison, Angela, Nelson, Garrett, and Vindas-Meléndez, Andrés R.

Subjects
Mathematics - Combinatorics, 05A10, 05A15, 05A19, 52B05, 52B11, 52B15, 52B20, 52B40
Abstract

For $\mathbf{b}=(b_1,\dots,b_n)\in \mathbb{Z}_{>0}^n$, a $\mathbf{b}$-parking function is defined to be a sequence $(\beta_1,\dots,\beta_n)$ of positive integers whose nondecreasing rearrangement $\beta'_1\leq \beta'_2\leq \cdots \leq \beta'_n$ satisfies $\beta'_i\leq b_1+\cdots + b_i$. The $\mathbf{b}$-parking-function polytope $\mathfrak{X}_n(\mathbf{b})$ is the convex hull of all $\mathbf{b}$-parking functions of length $n$ in $\mathbb{R}^n$. Geometric properties of $\mathfrak{X}_n(\mathbf{b})$ were previously explored in the specific case where $\mathbf{b}=(a,b,b,\dots,b)$ and were shown to generalize those of the classical parking-function polytope. In this work, we study $\mathfrak{X}_n(\mathbf{b})$ in full generality. We present a minimal inequality and vertex description for $\mathfrak{X}_n(\mathbf{b})$, prove it is a generalized permutahedron, and study its $h$-polynomial. Furthermore, we investigate $\mathfrak{X}_n(\mathbf{b})$ through the perspectives of building sets and polymatroids, allowing us to identify its combinatorial types and obtain bounds on its combinatorial and circuit diameters., Comment: 27 pages, 4 figures, Comments welcomed!

Published
2024

5. Detection of a Geminate Photoproduct of Bovine Cytochrome c Oxidase by Time-Resolved Serial Femtosecond Crystallography

Author

Ishigami, Izumi, Carbajo, Sergio, Zatsepin, Nadia, Hikita, Masahide, Conrad, Chelsie E, Nelson, Garrett, Coe, Jesse, Basu, Shibom, Grant, Thomas, Seaberg, Matthew H, Sierra, Raymond G, Hunter, Mark S, Fromme, Petra, Fromme, Raimund, Rousseau, Denis L, and Yeh, Syun-Ru

Subjects
Inorganic Chemistry, Chemical Sciences, Acquired Cognitive Impairment, Brain Disorders, Cattle, Animals, Electron Transport Complex IV, Oxidation-Reduction, Copper, Ligands, Oxygen, Crystallography, X-Ray, Iron, Water, General Chemistry, Chemical sciences, Engineering
Abstract

Cytochrome c oxidase (CcO) is a large membrane-bound hemeprotein that catalyzes the reduction of dioxygen to water. Unlike classical dioxygen binding hemeproteins with a heme b group in their active sites, CcO has a unique binuclear center (BNC) composed of a copper atom (CuB) and a heme a3 iron, where O2 binds and is reduced to water. CO is a versatile O2 surrogate in ligand binding and escape reactions. Previous time-resolved spectroscopic studies of the CO complexes of bovine CcO (bCcO) revealed that photolyzing CO from the heme a3 iron leads to a metastable intermediate (CuB-CO), where CO is bound to CuB, before it escapes out of the BNC. Here, with a pump-probe based time-resolved serial femtosecond X-ray crystallography, we detected a geminate photoproduct of the bCcO-CO complex, where CO is dissociated from the heme a3 iron and moved to a temporary binding site midway between the CuB and the heme a3 iron, while the locations of the two metal centers and the conformation of Helix-X, housing the proximal histidine ligand of the heme a3 iron, remain in the CO complex state. This new structure, combined with other reported structures of bCcO, allows for a clearer definition of the ligand dissociation trajectory as well as the associated protein dynamics.

Published
2023

6. Sampling planar tanglegrams and pairs of disjoint triangulations

Author

Black, Alexander E., Liu, Kevin, Mcdonough, Alex, Nelson, Garrett, Wigal, Michael C., Yin, Mei, and Yoo, Youngho

Subjects
Mathematics - Combinatorics, Mathematics - Probability, 05C05, 05C30
Abstract

A tanglegram consists of two rooted binary trees and a perfect matching between their leaves, and a planar tanglegram is one that admits a layout with no crossings. We show that the problem of generating planar tanglegrams uniformly at random reduces to the corresponding problem for irreducible planar tanglegram layouts, which are known to be in bijection with pairs of disjoint triangulations of a convex polygon. We extend the flip operation on a single triangulation to a flip operation on pairs of disjoint triangulations. Interestingly, the resulting flip graph is both connected and regular, and hence a random walk on this graph converges to the uniform distribution. We also show that the restriction of the flip graph to the pairs with a fixed triangulation in either coordinate is connected, and give diameter bounds that are near optimal. Our results furthermore yield new insight into the flip graph of triangulations of a convex $n$-gon with a geometric interpretation on the associahedron., Comment: 16 pages, 8 figures

Published
2023

7. Observation of substrate diffusion and ligand binding in enzyme crystals using high-repetition-rate mix-and-inject serial crystallography

Author

Pandey, Suraj, Calvey, George, Katz, Andrea M, Malla, Tek Narsingh, Koua, Faisal HM, Martin-Garcia, Jose M, Poudyal, Ishwor, Yang, Jay-How, Vakili, Mohammad, Yefanov, Oleksandr, Zielinski, Kara A, Bajt, Sasa, Awel, Salah, Doerner, Katarina, Frank, Matthias, Gelisio, Luca, Jernigan, Rebecca, Kirkwood, Henry, Kloos, Marco, Koliyadu, Jayanath, Mariani, Valerio, Miller, Mitchell D, Mills, Grant, Nelson, Garrett, Olmos, Jose L, Sadri, Alireza, Sato, Tokushi, Tolstikova, Alexandra, Xu, Weijun, Ourmazd, Abbas, Spence, John CH, Schwander, Peter, Barty, Anton, Chapman, Henry N, Fromme, Petra, Mancuso, Adrian P, Phillips, George N, Bean, Richard, Pollack, Lois, and Schmidt, Marius

Subjects
Tuberculosis, Rare Diseases, Good Health and Well Being, substrate diffusion in crystals, antibiotic resistance, beta-lactamases, enzyme kinetics, irreversible inhibition, mix-and-inject serial crystallography, serial femtosecond crystallography, European X-ray Free-Electron Laser, megahertz pulse-repetition rate, protein structure determination, drug discovery, ceftriaxone, sulbactam, X-ray crystallography, enzyme mechanisms, β-lactamases, Atomic, Molecular, Nuclear, Particle and Plasma Physics, Condensed Matter Physics, Physical Chemistry (incl. Structural)
Abstract

Here, we illustrate what happens inside the catalytic cleft of an enzyme when substrate or ligand binds on single-millisecond timescales. The initial phase of the enzymatic cycle is observed with near-atomic resolution using the most advanced X-ray source currently available: the European XFEL (EuXFEL). The high repetition rate of the EuXFEL combined with our mix-and-inject technology enables the initial phase of ceftriaxone binding to the Mycobacterium tuberculosis β-lactamase to be followed using time-resolved crystallography in real time. It is shown how a diffusion coefficient in enzyme crystals can be derived directly from the X-ray data, enabling the determination of ligand and enzyme-ligand concentrations at any position in the crystal volume as a function of time. In addition, the structure of the irreversible inhibitor sulbactam bound to the enzyme at a 66 ms time delay after mixing is described. This demonstrates that the EuXFEL can be used as an important tool for biomedically relevant research.

Published
2021

9. Enzyme intermediates captured “on the fly” by mix-and-inject serial crystallography

Author

Olmos, Jose L, Pandey, Suraj, Martin-Garcia, Jose M, Calvey, George, Katz, Andrea, Knoska, Juraj, Kupitz, Christopher, Hunter, Mark S, Liang, Mengning, Oberthuer, Dominik, Yefanov, Oleksandr, Wiedorn, Max, Heyman, Michael, Holl, Mark, Pande, Kanupriya, Barty, Anton, Miller, Mitchell D, Stern, Stephan, Roy-Chowdhury, Shatabdi, Coe, Jesse, Nagaratnam, Nirupa, Zook, James, Verburgt, Jacob, Norwood, Tyler, Poudyal, Ishwor, Xu, David, Koglin, Jason, Seaberg, Matthew H, Zhao, Yun, Bajt, Saša, Grant, Thomas, Mariani, Valerio, Nelson, Garrett, Subramanian, Ganesh, Bae, Euiyoung, Fromme, Raimund, Fung, Russell, Schwander, Peter, Frank, Matthias, White, Thomas A, Weierstall, Uwe, Zatsepin, Nadia, Spence, John, Fromme, Petra, Chapman, Henry N, Pollack, Lois, Tremblay, Lee, Ourmazd, Abbas, Phillips, George N, and Schmidt, Marius

Subjects
Biochemistry and Cell Biology, Biological Sciences, Rare Diseases, Infectious Diseases, Good Health and Well Being, Anti-Bacterial Agents, Bacterial Proteins, Biocatalysis, Ceftriaxone, Cephalosporin Resistance, Crystallography, X-Ray, Kinetics, Lasers, Models, Molecular, Mycobacterium tuberculosis, Time Factors, beta-Lactamases, Developmental Biology
Abstract

BackgroundEver since the first atomic structure of an enzyme was solved, the discovery of the mechanism and dynamics of reactions catalyzed by biomolecules has been the key goal for the understanding of the molecular processes that drive life on earth. Despite a large number of successful methods for trapping reaction intermediates, the direct observation of an ongoing reaction has been possible only in rare and exceptional cases.ResultsHere, we demonstrate a general method for capturing enzyme catalysis "in action" by mix-and-inject serial crystallography (MISC). Specifically, we follow the catalytic reaction of the Mycobacterium tuberculosis β-lactamase with the third-generation antibiotic ceftriaxone by time-resolved serial femtosecond crystallography. The results reveal, in near atomic detail, antibiotic cleavage and inactivation from 30 ms to 2 s.ConclusionsMISC is a versatile and generally applicable method to investigate reactions of biological macromolecules, some of which are of immense biological significance and might be, in addition, important targets for structure-based drug design. With megahertz X-ray pulse rates expected at the Linac Coherent Light Source II and the European X-ray free-electron laser, multiple, finely spaced time delays can be collected rapidly, allowing a comprehensive description of biomolecular reactions in terms of structure and kinetics from the same set of X-ray data.

Published
2018

13. Structural enzymology using X-ray free electron lasers

Author

Kupitz, Christopher, Olmos, Jose L, Holl, Mark, Tremblay, Lee, Pande, Kanupriya, Pandey, Suraj, Oberthür, Dominik, Hunter, Mark, Liang, Mengning, Aquila, Andrew, Tenboer, Jason, Calvey, George, Katz, Andrea, Chen, Yujie, Wiedorn, Max O, Knoska, Juraj, Meents, Alke, Majriani, Valerio, Norwood, Tyler, Poudyal, Ishwor, Grant, Thomas, Miller, Mitchell D, Xu, Weijun, Tolstikova, Aleksandra, Morgan, Andrew, Metz, Markus, Martin-Garcia, Jose M, Zook, James D, Roy-Chowdhury, Shatabdi, Coe, Jesse, Nagaratnam, Nirupa, Meza, Domingo, Fromme, Raimund, Basu, Shibom, Frank, Matthias, White, Thomas, Barty, Anton, Bajt, Sasa, Yefanov, Oleksandr, Chapman, Henry N, Zatsepin, Nadia, Nelson, Garrett, Weierstall, Uwe, Spence, John, Schwander, Peter, Pollack, Lois, Fromme, Petra, Ourmazd, Abbas, Phillips, George N, and Schmidt, Marius

Subjects
Inorganic Chemistry, Chemical Sciences, Physical Sciences, Infectious Diseases, Good Health and Well Being, Physical chemistry, Condensed matter physics, Particle and high energy physics
Abstract

Mix-and-inject serial crystallography (MISC) is a technique designed to image enzyme catalyzed reactions in which small protein crystals are mixed with a substrate just prior to being probed by an X-ray pulse. This approach offers several advantages over flow cell studies. It provides (i) room temperature structures at near atomic resolution, (ii) time resolution ranging from microseconds to seconds, and (iii) convenient reaction initiation. It outruns radiation damage by using femtosecond X-ray pulses allowing damage and chemistry to be separated. Here, we demonstrate that MISC is feasible at an X-ray free electron laser by studying the reaction of M. tuberculosis ß-lactamase microcrystals with ceftriaxone antibiotic solution. Electron density maps of the apo-ß-lactamase and of the ceftriaxone bound form were obtained at 2.8 Å and 2.4 Å resolution, respectively. These results pave the way to study cyclic and non-cyclic reactions and represent a new field of time-resolved structural dynamics for numerous substrate-triggered biological reactions.

Published
2017

17. Ultrafast structural changes within a photosynthetic reaction centre

Author

Dods, Robert, Båth, Petra, Morozov, Dmitry, Gagnér, Viktor Ahlberg, Arnlund, David, Luk, Hoi Ling, Kübel, Joachim, Maj, Michał, Vallejos, Adams, Wickstrand, Cecilia, Bosman, Robert, Beyerlein, Kenneth R., Nelson, Garrett, Liang, Mengning, Milathianaki, Despina, Robinson, Joseph, Harimoorthy, Rajiv, Berntsen, Peter, Malmerberg, Erik, Johansson, Linda, Andersson, Rebecka, Carbajo, Sergio, Claesson, Elin, Conrad, Chelsie E., Dahl, Peter, Hammarin, Greger, Hunter, Mark S., Li, Chufeng, Lisova, Stella, Royant, Antoine, Safari, Cecilia, Sharma, Amit, Williams, Garth J., Yefanov, Oleksandr, Westenhoff, Sebastian, Davidsson, Jan, DePonte, Daniel P., Boutet, Sébastien, Barty, Anton, Katona, Gergely, Groenhof, Gerrit, Brändén, Gisela, and Neutze, Richard

Published
2021
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18. Lipidic cubic phase injector is a viable crystal delivery system for time-resolved serial crystallography

Author

Nogly, Przemyslaw, Panneels, Valerie, Nelson, Garrett, Gati, Cornelius, Kimura, Tetsunari, Milne, Christopher, Milathianaki, Despina, Kubo, Minoru, Wu, Wenting, Conrad, Chelsie, Coe, Jesse, Bean, Richard, Zhao, Yun, Båth, Petra, Dods, Robert, Harimoorthy, Rajiv, Beyerlein, Kenneth R, Rheinberger, Jan, James, Daniel, DePonte, Daniel, Li, Chufeng, Sala, Leonardo, Williams, Garth J, Hunter, Mark S, Koglin, Jason E, Berntsen, Peter, Nango, Eriko, Iwata, So, Chapman, Henry N, Fromme, Petra, Frank, Matthias, Abela, Rafael, Boutet, Sébastien, Barty, Anton, White, Thomas A, Weierstall, Uwe, Spence, John, Neutze, Richard, Schertler, Gebhard, and Standfuss, Jörg

Subjects
Chemical Sciences, Physical Chemistry, Bioengineering, Nanotechnology, Bacteriorhodopsins, Crystallography, X-Ray, Feasibility Studies, Lasers, Lipids, Protein Conformation, Synchrotrons, Time Factors, Viscosity, X-Ray Absorption Spectroscopy
Abstract

Serial femtosecond crystallography (SFX) using X-ray free-electron laser sources is an emerging method with considerable potential for time-resolved pump-probe experiments. Here we present a lipidic cubic phase SFX structure of the light-driven proton pump bacteriorhodopsin (bR) to 2.3 Å resolution and a method to investigate protein dynamics with modest sample requirement. Time-resolved SFX (TR-SFX) with a pump-probe delay of 1 ms yields difference Fourier maps compatible with the dark to M state transition of bR. Importantly, the method is very sample efficient and reduces sample consumption to about 1 mg per collected time point. Accumulation of M intermediate within the crystal lattice is confirmed by time-resolved visible absorption spectroscopy. This study provides an important step towards characterizing the complete photocycle dynamics of retinal proteins and demonstrates the feasibility of a sample efficient viscous medium jet for TR-SFX.

Published
2016

19. Snapshot of an oxygen intermediate in the catalytic reaction of cytochrome c oxidase

Author

Ishigami, Izumi, Lewis-Ballester, Ariel, Echelmeier, Austin, Brehm, Gerrit, Zatsepin, Nadia A., Grant, Thomas D., Coe, Jesse D., Lisova, Stella, Nelson, Garrett, Zhang, Shangji, Dobson, Zachary F., Boutet, Sébastien, Sierra, Raymond G., Batyuk, Alexander, Fromme, Petra, Fromme, Raimund, Spence, John C. H., Ros, Alexandra, Yeh, Syun-Ru, and Rousseau, Denis L.

Published
2019

26. Detection of a geminate photoproduct of bovine cytochrome c oxidase by time-resolved serial femtosecond crystallography

Author

Ishigami, Izumi, primary, Carbajo, Sergio, additional, Zatsepin, Nadia, additional, Hikita, Masahide, additional, Conrad, Chelsie E., additional, Nelson, Garrett, additional, Coe, Jesse, additional, Basu, Shibom, additional, Grant, Thomas, additional, Seaberg, Matthew H., additional, Sierra, Raymond G., additional, Hunter, Mark S., additional, Fromme, Petra, additional, Fromme, Raimund, additional, Rousseau, Denis L., additional, and Yeh, Syun-Ru, additional

Published
2023
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30. Modular droplet injector for sample conservation providing new structural insight for the conformational heterogeneity in the disease-associated NQO1 enzyme

Author

National Science Foundation (US), National Institutes of Health (US), Department of Energy (US), Max Planck Institute for Medical Research, Comunidad de Madrid, Ministerio de Ciencia, Innovación y Universidades (España), Junta de Andalucía, Doppler, Diandra [0000-0002-3586-3936], Sonker, Mukul [0000-0001-5816-8410], Egatz-Gomez, Ana [0000-0002-6080-943X], Manna, Abhik [0000-0001-8681-6702], Cruz Villarreal, Jorvani [0000-0002-6762-7348], Pey, Angel L. [0000-0001-7706-3243], Ruiz-Fresneda, Miguel A. [0000-0001-6349-6566], Pacheco-Garcia, Juan Luis [0000-0001-6043-7536], Hermoso, Juan A. [0000-0002-1862-8950], Batyuk, Alexander [0000-0002-9393-2880], Fromme, Raimund [0000-0003-4835-1080], Kirian, Richard A. [0000-0001-7197-3086], Martín-García, José M. [0000-0002-4558-3858], Ros, Alexandra [0000-0001-7709-8331], Doppler, Diandra, Sonker, Mukul, Egatz-Gomez, Ana, Grieco, Alice, Zaare, Sahba, Jernigan, Rebecca, Meza-Aguilar, Jose Domingo, Rabbani, Mohammad T., Manna, Abhik, Alvarez, Roberto C., Karpos, Konstantinos, Cruz Villarreal, Jorvani, Nelson, Garrett, Yang, Jay-How, Carrion, Jackson, Morin, Katherine, Ketawala, Gihan K, Pey, Angel L., Ruiz-Fresneda, Miguel A., Pacheco-Garcia, Juan Luis, Hermoso, Juan A., Nazari, Reza, Sierra, Raymond, Hunter, Mark S., Batyuk, Alexander, Kupitz, Christopher J., Sublett, Robert E., Lisova, Stella, Mariani, Valerio, Boutet, Sébastien, Fromme, Raimund, Grant, Thomas D., Botha, Sabine, Fromme, Petra, Kirian, Richard A., Martín-García, José M., Ros, Alexandra, National Science Foundation (US), National Institutes of Health (US), Department of Energy (US), Max Planck Institute for Medical Research, Comunidad de Madrid, Ministerio de Ciencia, Innovación y Universidades (España), Junta de Andalucía, Doppler, Diandra [0000-0002-3586-3936], Sonker, Mukul [0000-0001-5816-8410], Egatz-Gomez, Ana [0000-0002-6080-943X], Manna, Abhik [0000-0001-8681-6702], Cruz Villarreal, Jorvani [0000-0002-6762-7348], Pey, Angel L. [0000-0001-7706-3243], Ruiz-Fresneda, Miguel A. [0000-0001-6349-6566], Pacheco-Garcia, Juan Luis [0000-0001-6043-7536], Hermoso, Juan A. [0000-0002-1862-8950], Batyuk, Alexander [0000-0002-9393-2880], Fromme, Raimund [0000-0003-4835-1080], Kirian, Richard A. [0000-0001-7197-3086], Martín-García, José M. [0000-0002-4558-3858], Ros, Alexandra [0000-0001-7709-8331], Doppler, Diandra, Sonker, Mukul, Egatz-Gomez, Ana, Grieco, Alice, Zaare, Sahba, Jernigan, Rebecca, Meza-Aguilar, Jose Domingo, Rabbani, Mohammad T., Manna, Abhik, Alvarez, Roberto C., Karpos, Konstantinos, Cruz Villarreal, Jorvani, Nelson, Garrett, Yang, Jay-How, Carrion, Jackson, Morin, Katherine, Ketawala, Gihan K, Pey, Angel L., Ruiz-Fresneda, Miguel A., Pacheco-Garcia, Juan Luis, Hermoso, Juan A., Nazari, Reza, Sierra, Raymond, Hunter, Mark S., Batyuk, Alexander, Kupitz, Christopher J., Sublett, Robert E., Lisova, Stella, Mariani, Valerio, Boutet, Sébastien, Fromme, Raimund, Grant, Thomas D., Botha, Sabine, Fromme, Petra, Kirian, Richard A., Martín-García, José M., and Ros, Alexandra

Abstract

Droplet injection strategies are a promising tool to reduce the large amount of sample consumed in serial femtosecond crystallography (SFX) measurements at X-ray free electron lasers (XFELs) with continuous injection approaches. Here, we demonstrate a new modular microfluidic droplet injector (MDI) design that was successfully applied to deliver microcrystals of the human NAD(P)H:quinone oxidoreductase 1 (NQO1) and phycocyanin. We investigated droplet generation conditions through electrical stimulation for both protein samples and implemented hardware and software components for optimized crystal injection at the Macromolecular Femtosecond Crystallography (MFX) instrument at the Stanford Linac Coherent Light Source (LCLS). Under optimized droplet injection conditions, we demonstrate that up to 4-fold sample consumption savings can be achieved with the droplet injector. In addition, we collected a full data set with droplet injection for NQO1 protein crystals with a resolution up to 2.7 Å, leading to the first room-temperature structure of NQO1 at an XFEL. NQO1 is a flavoenzyme associated with cancer, Alzheimer's and Parkinson's disease, making it an attractive target for drug discovery. Our results reveal for the first time that residues Tyr128 and Phe232, which play key roles in the function of the protein, show an unexpected conformational heterogeneity at room temperature within the crystals. These results suggest that different substates exist in the conformational ensemble of NQO1 with functional and mechanistic implications for the enzyme's negative cooperativity through a conformational selection mechanism. Our study thus demonstrates that microfluidic droplet injection constitutes a robust sample-conserving injection method for SFX studies on protein crystals that are difficult to obtain in amounts necessary for continuous injection, including the large sample quantities required for time-resolved mix-and-inject studies.

Published
2023

33. Modular droplet injector for sample conservation providing new structural insight for the conformational heterogeneity in the disease-associated NQO1 enzyme

Author

Doppler, Diandra, primary, Sonker, Mukul, additional, Egatz-Gomez, Ana, additional, Grieco, Alice, additional, Zaare, Sahba, additional, Jernigan, Rebecca, additional, Meza-Aguilar, Jose Domingo, additional, Rabbani, Mohammad T., additional, Manna, Abhik, additional, Alvarez, Roberto C., additional, Karpos, Konstantinos, additional, Cruz Villarreal, Jorvani, additional, Nelson, Garrett, additional, Yang, Jay-How, additional, Carrion, Jackson, additional, Morin, Katherine, additional, Ketawala, Gihan K., additional, Pey, Angel L., additional, Ruiz-Fresneda, Miguel Angel, additional, Pacheco-Garcia, Juan Luis, additional, Hermoso, Juan A., additional, Nazari, Reza, additional, Sierra, Raymond, additional, Hunter, Mark S., additional, Batyuk, Alexander, additional, Kupitz, Christopher J., additional, Sublett, Robert E., additional, Lisova, Stella, additional, Mariani, Valerio, additional, Boutet, Sébastien, additional, Fromme, Raimund, additional, Grant, Thomas D., additional, Botha, Sabine, additional, Fromme, Petra, additional, Kirian, Richard A., additional, Martin-Garcia, Jose Manuel, additional, and Ros, Alexandra, additional

Published
2023
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35. Electrically stimulated droplet injector for reduced sample consumption in serial crystallography

Author

Sonker, Mukul, primary, Doppler, Diandra, additional, Egatz-Gomez, Ana, additional, Zaare, Sahba, additional, Rabbani, Mohammad T., additional, Manna, Abhik, additional, Cruz Villarreal, Jorvani, additional, Nelson, Garrett, additional, Ketawala, Gihan K., additional, Karpos, Konstantinos, additional, Alvarez, Roberto C., additional, Nazari, Reza, additional, Thifault, Darren, additional, Jernigan, Rebecca, additional, Oberthür, Dominik, additional, Han, Huijong, additional, Sierra, Raymond, additional, Hunter, Mark S., additional, Batyuk, Alexander, additional, Kupitz, Christopher J., additional, Sublett, Robert E., additional, Poitevin, Frederic, additional, Lisova, Stella, additional, Mariani, Valerio, additional, Tolstikova, Alexandra, additional, Boutet, Sebastien, additional, Messerschmidt, Marc, additional, Meza-Aguilar, J. Domingo, additional, Fromme, Raimund, additional, Martin-Garcia, Jose M., additional, Botha, Sabine, additional, Fromme, Petra, additional, Grant, Thomas D., additional, Kirian, Richard A., additional, and Ros, Alexandra, additional

Published
2022
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36. Structure of the full-length glucagon class B G-protein-coupled receptor

Author

Zhang, Haonan, Qiao, Anna, Yang, Dehua, Yang, Linlin, Dai, Antao, de Graaf, Chris, Reedtz-Runge, Steffen, Dharmarajan, Venkatasubramanian, Zhang, Hui, Han, Gye Won, Grant, Thomas D., Sierra, Raymond G., Weierstall, Uwe, Nelson, Garrett, Liu, Wei, Wu, Yanhong, Ma, Limin, Cai, Xiaoqing, Lin, Guangyao, Wu, Xiaoai, Geng, Zhi, Dong, Yuhui, Song, Gaojie, Griffin, Patrick R., Lau, Jesper, Cherezov, Vadim, Yang, Huaiyu, Hanson, Michael A., Stevens, Raymond C., Zhao, Qiang, Jiang, Hualiang, Wang, Ming-Wei, and Wu, Beili

Published
2017
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42. Serial Femtosecond Crystallography of G Protein-Coupled Receptors

Author

Liu, Wei, Wacker, Daniel, Gati, Cornelius, Han, Gye Won, James, Daniel, Wang, Dingjie, Nelson, Garrett, Weierstall, Uwe, Katritch, Vsevolod, Barty, Anton, Zatsepin, Nadia A., Li, Dianfan, Messerschmidt, Marc, Boutet, Sébastien, Williams, Garth J., Koglin, Jason E., Seibert, M. Marvin, Wang, Chong, Shah, Syed T. A., Basu, Shibom, Fromme, Raimund, Kupitz, Christopher, Rendek, Kimberley N., Grotjohann, Ingo, Fromme, Petra, Kirian, Richard A., Beyerlein, Kenneth R., White, Thomas A., Chapman, Henry N., Caffrey, Martin, Spence, John C. H., Stevens, Raymond C., and Cherezov, Vadim

Published
2013
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43. Detection of a Geminate Photoproduct of Bovine Cytochrome cOxidase by Time-Resolved Serial Femtosecond Crystallography

Author

Ishigami, Izumi, Carbajo, Sergio, Zatsepin, Nadia, Hikita, Masahide, Conrad, Chelsie E., Nelson, Garrett, Coe, Jesse, Basu, Shibom, Grant, Thomas, Seaberg, Matthew H., Sierra, Raymond G., Hunter, Mark S., Fromme, Petra, Fromme, Raimund, Rousseau, Denis L., and Yeh, Syun-Ru

Abstract

Cytochrome coxidase (CcO) is a large membrane-bound hemeprotein that catalyzes the reduction of dioxygen to water. Unlike classical dioxygen binding hemeproteins with a heme bgroup in their active sites, CcO has a unique binuclear center (BNC) composed of a copper atom (CuB) and a heme a3iron, where O2binds and is reduced to water. CO is a versatile O2surrogate in ligand binding and escape reactions. Previous time-resolved spectroscopic studies of the CO complexes of bovine CcO (bCcO) revealed that photolyzing CO from the heme a3iron leads to a metastable intermediate (CuB-CO), where CO is bound to CuB, before it escapes out of the BNC. Here, with a pump-probe based time-resolved serial femtosecond X-ray crystallography, we detected a geminate photoproduct of the bCcO–CO complex, where CO is dissociated from the heme a3iron and moved to a temporary binding site midway between the CuBand the heme a3iron, while the locations of the two metal centers and the conformation of Helix-X, housing the proximal histidine ligand of the heme a3iron, remain in the CO complex state. This new structure, combined with other reported structures of bCcO, allows for a clearer definition of the ligand dissociation trajectory as well as the associated protein dynamics.

Published
2023
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44. Electrically stimulated droplet injector for reduced sample consumption in serial crystallography

Author

National Science Foundation (US), National Institutes of Health (US), Department of Energy (US), Max Planck Institute for Medical Research, Sonker, Mukul, Doppler, Diandra, Egatz-Gomez, Ana, Zaare, Sahba, Rabbani, Mohammad T., Manna, Abhik, Cruz Villarreal, Jorvani, Nelson, Garrett, Ketawala, Gihan K., Karpos, Konstantinos, Alvarez, Roberto C., Nazari, Reza, Thifault, Darren, Jernigan, Rebecca, Oberthür, Dominik, Han, Huijong, Sierra, Raymond, Hunter, Mark S., Batyuk, Alexander, Kupitz, Christopher J., Sublett, Robert E., Poitevin, Frederic, Lisova, Stella, Mariani, Valerio, Tolstikova, Alexandra, Boutet, Sebastien, Messerschmidt, Marc, Meza-Aguilar, J Domingo, Fromme, Raimund, Martín-García, Jose Manuel, Botha, Sabine, Fromme, Petra, Grant, Thomas D., Kirian, Richard A., Ros, Alexandra, National Science Foundation (US), National Institutes of Health (US), Department of Energy (US), Max Planck Institute for Medical Research, Sonker, Mukul, Doppler, Diandra, Egatz-Gomez, Ana, Zaare, Sahba, Rabbani, Mohammad T., Manna, Abhik, Cruz Villarreal, Jorvani, Nelson, Garrett, Ketawala, Gihan K., Karpos, Konstantinos, Alvarez, Roberto C., Nazari, Reza, Thifault, Darren, Jernigan, Rebecca, Oberthür, Dominik, Han, Huijong, Sierra, Raymond, Hunter, Mark S., Batyuk, Alexander, Kupitz, Christopher J., Sublett, Robert E., Poitevin, Frederic, Lisova, Stella, Mariani, Valerio, Tolstikova, Alexandra, Boutet, Sebastien, Messerschmidt, Marc, Meza-Aguilar, J Domingo, Fromme, Raimund, Martín-García, Jose Manuel, Botha, Sabine, Fromme, Petra, Grant, Thomas D., Kirian, Richard A., and Ros, Alexandra

Abstract

With advances in X-ray free-electron lasers (XFELs), serial femtosecond crystallography (SFX) has enabled the static and dynamic structure determination for challenging proteins such as membrane protein complexes. In SFX with XFELs, the crystals are typically destroyed after interacting with a single XFEL pulse. Therefore, thousands of new crystals must be sequentially introduced into the X-ray beam to collect full data sets. Because of the serial nature of any SFX experiment, up to 99% of the sample delivered to the X-ray beam during its "off-time" between X-ray pulses is wasted due to the intrinsic pulsed nature of all current XFELs. To solve this major problem of large and often limiting sample consumption, we report on improvements of a revolutionary sample-saving method that is compatible with all current XFELs. We previously reported 3D-printed injection devices coupled with gas dynamic virtual nozzles (GDVNs) capable of generating samples containing droplets segmented by an immiscible oil phase for jetting crystal-laden droplets into the path of an XFEL. Here, we have further improved the device design by including metal electrodes inducing electrowetting effects for improved control over droplet generation frequency to stimulate the droplet release to matching the XFEL repetition rate by employing an electrical feedback mechanism. We report the improvements in this electrically triggered segmented flow approach for sample conservation in comparison with a continuous GDVN injection using the microcrystals of lysozyme and 3-deoxy-D-manno-octulosonate 8-phosphate synthase and report the segmented flow approach for sample injection applied at the Macromolecular Femtosecond Crystallography instrument at the Linear Coherent Light Source for the first time.

Published
2022

50. Macromolecular diffractive imaging using imperfect crystals

Author

Ayyer, Kartik, Yefanov, Oleksandr M., Oberthür, Dominik, Roy-Chowdhury, Shatabdi, Galli, Lorenzo, Mariani, Valerio, Basu, Shibom, Coe, Jesse, Conrad, Chelsie E., Fromme, Raimund, Schaffer, Alexander, Dörner, Katerina, James, Daniel, Kupitz, Christopher, Metz, Markus, Nelson, Garrett, Xavier, Paulraj Lourdu, Beyerlein, Kenneth R., Schmidt, Marius, Sarrou, Iosifina, Spence, John C. H., Weierstall, Uwe, White, Thomas A., Yang, Jay-How, Zhao, Yun, Liang, Mengning, Aquila, Andrew, Hunter, Mark S., Robinson, Joseph S., Koglin, Jason E., Boutet, Sébastien, Fromme, Petra, Barty, Anton, and Chapman, Henry N.

Published
2016
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