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51. High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer

Author

Palafox, Marta, primary, Monserrat, Laia, additional, Bellet, Meritxell, additional, Villacampa, Guillermo, additional, Gonzalez-Perez, Abel, additional, Oliveira, Mafalda, additional, Brasó-Maristany, Fara, additional, Ibrahimi, Nusaibah, additional, Kannan, Srinivasaraghavan, additional, Mina, Leonardo, additional, Herrera-Abreu, María Teresa, additional, Ódena, Andreu, additional, Sánchez-Guixé, Mónica, additional, Capelán, Marta, additional, Azaro, Analía, additional, Bruna, Alejandra, additional, Rodriguez, Olga, additional, Guzmán, Marta, additional, Grueso, Judit, additional, Viaplana, Cristina, additional, Hernandez-Losa, Javier, additional, Su, Faye, additional, Lin, Kui, additional, Clarke, Robert (B.), additional, Caldas, Carlos, additional, Joaquín, Arribas, additional, Michiels, Stefan, additional, García-Sanz, Alicia, additional, Turner, Nicholas C., additional, Prat, Aleix, additional, Nuciforo, Paolo, additional, Dienstmann, Rodgrigo, additional, Verma, Chandra, additional, López-Bigas, Núria, additional, Scaltriti, Maurizio, additional, Arnedos, Monica, additional, Saura, Cristina, additional, and Serra, Violeta, additional

Published
2021
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53. Conformational landscape of the epidermal growth factor receptor kinase reveals a mutant specific allosteric pocket† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c8sc01262h

Author

Kannan, Srinivasaraghavan, Venkatachalam, Gireedhar, Lim, Hong Hwa, Surana, Uttam, and Verma, Chandra

Subjects
Chemistry
Abstract

An oncogenic mutant-specific druggable allosteric pocket captured by MD simulations., Activating mutations within the epidermal growth factor receptor (EGFR) kinase domain give rise to several cancers including Non-Small Cell Lung Cancer (NSCLC). Small molecule inhibitors targeted at these mutants have proven to be clinically successful drugs. These molecules are ATP competitive and rapidly result in the emergence of resistance. Recently Jia et al. [Nature, 2016, 534, 129–132] reported a small molecule inhibitor (called EAI045) that binds at an allosteric pocket, does not compete with ATP and displays high potency and selectivity towards certain activating mutants (L858R, T790M, L858R/T790M) of EGFR, with IC50 values ranging from 3 nM to 49 nM. We present here a study combining extensive molecular dynamics simulations with binding assays to provide a structural basis underlying the mechanism of binding of this molecule. It appears that in mutants, conformational destabilization of the short helix (that carries Leu858 in the wildtype), is key to the exposure of the allosteric pocket which otherwise is occluded by a set of sidechains including L858. We extend this hypothesis to show that a similar mechanism would enable the molecule to inhibit EGFRL861Q which is another oncogenic mutant and validate this with binding experiments. The screening of the human structural kinome revealed at least 12 other oncogenic kinases which carry at least one activating mutant in this disorder-prone region and hence would be amenable to allosteric inhibition by molecules such as EAI045. Our study characterizes a druggable allosteric pocket which appears to be specific to certain oncogenic mutants of the EGFR and holds therapeutic potential.

Published
2018

55. TRK xDFG Mutations Trigger a Sensitivity Switch from Type I to II Kinase Inhibitors

Author

Cocco, Emiliano, primary, Lee, Ji Eun, additional, Kannan, Srinivasaraghavan, additional, Schram, Alison M., additional, Won, Helen H., additional, Shifman, Sophie, additional, Kulick, Amanda, additional, Baldino, Laura, additional, Toska, Eneda, additional, Arruabarrena-Aristorena, Amaia, additional, Kittane, Srushti, additional, Wu, Fan, additional, Cai, Yanyan, additional, Arena, Sabrina, additional, Mussolin, Benedetta, additional, Kannan, Ram, additional, Vasan, Neil, additional, Gorelick, Alexander N., additional, Berger, Michael F., additional, Novoplansky, Ofra, additional, Jagadeeshan, Sankar, additional, Liao, Yi, additional, Rix, Uwe, additional, Misale, Sandra, additional, Taylor, Barry S., additional, Bardelli, Alberto, additional, Hechtman, Jaclyn F., additional, Hyman, David M., additional, Elkabets, Moshe, additional, de Stanchina, Elisa, additional, Verma, Chandra S., additional, Ventura, Andrea, additional, Drilon, Alexander, additional, and Scaltriti, Maurizio, additional

Published
2021
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57. Exploitation of dihydroorotate dehydrogenase (DHODH) and p53 activation as therapeutic targets: A case study in polypharmacology

Author

Ladds, Marcus J. G.W., primary, Popova, Gergana, additional, Pastor-Fernández, Andrés, additional, Kannan, Srinivasaraghavan, additional, van Leeuwen, Ingeborg M.M., additional, Håkansson, Maria, additional, Walse, Björn, additional, Tholander, Fredrik, additional, Bhatia, Ravi, additional, Verma, Chandra S., additional, Lane, David P., additional, and Laín, Sonia, additional

Published
2020
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59. FOXA1 Mutations Reveal Distinct Chromatin Profiles and Influence Therapeutic Response in Breast Cancer

Author

Arruabarrena-Aristorena, Amaia, primary, Maag, Jesper L.V., additional, Kittane, Srushti, additional, Cai, Yanyan, additional, Karthaus, Wouter R., additional, Ladewig, Erik, additional, Park, Jane, additional, Kannan, Srinivasaraghavan, additional, Ferrando, Lorenzo, additional, Cocco, Emiliano, additional, Ho, Sik Y., additional, Tan, Daisylyn S., additional, Sallaku, Mirna, additional, Wu, Fan, additional, Acevedo, Barbara, additional, Selenica, Pier, additional, Ross, Dara S., additional, Witkin, Matthew, additional, Sawyers, Charles L., additional, Reis-Filho, Jorge S., additional, Verma, Chandra S., additional, Jauch, Ralf, additional, Koche, Richard, additional, Baselga, José, additional, Razavi, Pedram, additional, Toska, Eneda, additional, and Scaltriti, Maurizio, additional

Published
2020
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60. Critical Role for Cold Shock Protein YB-1 in Cytokinesis

Author

Mehta, Sunali, primary, Algie, Michael, additional, Al-Jabry, Tariq, additional, McKinney, Cushla, additional, Kannan, Srinivasaraghavan, additional, Verma, Chandra S, additional, Ma, Weini, additional, Zhang, Jessie, additional, Bartolec, Tara K., additional, Masamsetti, V. Pragathi, additional, Parker, Kim, additional, Henderson, Luke, additional, Gould, Maree L, additional, Bhatia, Puja, additional, Harfoot, Rhodri, additional, Chircop, Megan, additional, Kleffmann, Torsten, additional, Cohen, Scott B, additional, Woolley, Adele G, additional, Cesare, Anthony J, additional, and Braithwaite, Antony, additional

Published
2020
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61. Abstract 3439: FOXA1 mutations reveal distinct chromatin profiles and influence therapeutic response in breast cancer

Author

Arruabarrena-Aristorena, Amaia, primary, Maag, Jesper LV, additional, Kittane, Srushti, additional, Cai, Yanyan, additional, Park, Jane, additional, Razavi, Pedram, additional, Ferrando, Lorenzo, additional, Selenica, Pier, additional, Karthaus, Wouter R., additional, Kannan, Srinivasaraghavan, additional, Cocco, Emiliano, additional, Ho, Sik Y., additional, Tan, Daisylyn Senna, additional, Sallaku, Mirna, additional, Sawyers, Charles L., additional, Reis-Fihlo, Jorge S., additional, Verma, Chandra S., additional, Jauch, Ralf, additional, Koche, Richard, additional, Baselga, José, additional, Toska, Eneda, additional, and Scaltriti, Maurizio, additional

Published
2020
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62. Abstract 5680: TRK xDFG mutations trigger a sensitivity switch from type I to II kinase inhibitors

Author

Cocco, Emiliano, primary, Lee, Ji Eun, additional, Kannan, Srinivasaraghavan, additional, Schram, Alison M., additional, Won, Helen H., additional, Shifman, Sophie, additional, Kulick, Amanda, additional, Baldino, Laura, additional, Toska, Eneda, additional, Arena, Sabrina, additional, Mussolin, Benedetta, additional, Kannan, Ram, additional, Vasan, Neil, additional, Gorelick, Alexander N., additional, Berger, Michael F., additional, Liao, Yi, additional, Rix, Uwe, additional, Bardelli, Alberto, additional, Hechtman, Jacklyn, additional, de Stanchina, Elisa, additional, Hyman, David M., additional, Verma, Chandra, additional, Ventura, Andrea, additional, Drilon, Alexander, additional, and Scaltriti, Maurizio, additional

Published
2020
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64. De-risking Drug Discovery of Intracellular Targeting Peptides: Screening Strategies to Eliminate False-Positive Hits

Author

Ng, Simon, primary, Juang, Yu-Chi, additional, Chandramohan, Arun, additional, Kaan, Hung Yi Kristal, additional, Sadruddin, Ahmad, additional, Yuen, Tsz Ying, additional, Ferrer-Gago, Fernando J., additional, Lee, Xue’Er Cheryl, additional, Liew, Xi, additional, Johannes, Charles W., additional, Brown, Christopher J., additional, Kannan, Srinivasaraghavan, additional, Aronica, Pietro G., additional, Berglund, Nils A., additional, Verma, Chandra S., additional, Liu, Lijuan, additional, Stoeck, Alexander, additional, Sawyer, Tomi K., additional, Partridge, Anthony W., additional, and Lane, David P., additional

Published
2020
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65. Dephosphorylation of YB-1 is Required for Nuclear Localisation During G2 Phase of the Cell Cycle

Author

Mehta, Sunali, primary, McKinney, Cushla, additional, Algie, Michael, additional, Verma, Chandra S., additional, Kannan, Srinivasaraghavan, additional, Harfoot, Rhodri, additional, Bartolec, Tara K., additional, Bhatia, Puja, additional, Fisher, Alistair J., additional, Gould, Maree L., additional, Parker, Kim, additional, Cesare, Anthony J., additional, Cunliffe, Heather E., additional, Cohen, Scott B., additional, Kleffmann, Torsten, additional, Braithwaite, Antony W., additional, and Woolley, Adele G., additional

Published
2020
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68. Macrocyclization of an all-D linear peptide improves target affinity and imparts cellular activity: A novel stapled α-helical peptide modality

Author

Kannan, Srinivasaraghavan, Aronica, Pietro G. A., Ng, Simon, Thean, Dawn, Frosi, Yuri, Chee, Sharon, Shimin, Jiang, Yuen, Tsz Ying, Sadruddin, Ahmad, Kaan, Hung Yi Kristal, Chandramohan, Arun, Wong, Jin Huei, Tan, Yaw Sing, Ferrer, Fernando J., Arumugam, Prakash, Han, Yi, Chen, Shiying, Brown, Christopher J., Johannes, Charles W., Henry, Brian, Lane, David P., Sawyer, Tomi K., Verma, Chandra S., and Partridge, Anthony W.

Abstract

Peptide-based inhibitors hold great potential for targeted modulation of intracellular protein-protein interactions (PPIs) by leveraging vast chemical space relative to primary structure via sequence diversity as well as conformationally through varying secondary and tertiary structures. However, the development of peptide therapeutics has been hindered because of their limited conformational stability, proteolytic sensitivity and cell permeability. Several contemporary peptide design strategies address these issues to varying degrees. Strategic macrocyclization through optimally placed chemical braces such as olefinic hydrocarbon crosslinks, commonly referred to as staples, may address these issues by i) restricting conformational freedom to improve target affinities, ii) improving proteolytic resistance, and iii) enhancing cell permeability. Conversely, molecules constructed entirely from D-amino acids are hyper-resistant to proteolytic cleavage, but generally lack conformational stability and membrane permeability. Since neither approach is a complete solution, we have combined these strategies to identify the first examples of all-D α-helical stapled and stitched peptides. As a template, we used a recently reported all D-linear peptide that is a potent inhibitor of the p53-Mdm2 interaction, but is devoid of cellular activity. To design both stapled and stitched all-D-peptide analogues, we used computational modelling to predict optimal staple placement. The resultant novel macrocyclic all D-peptide was determined to exhibit increased α-helicity, improved target binding, complete proteolytic stability and, most notably, cellular activity.

Published
2019
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69. Molecular basis for dengue virus broad cross-neutralization by humanized monoclonal antibody 513

Author

Chong Wai Liew, Akshita Kumar, Kannan Srinivasaraghavan, Yee Hwa Wong, Julien Lescar, Kannan Tharakaraman, Ram Sasisekharan, Chandra S. Verma, School of Biological Sciences, NTU Institute of Structural Biology, Massachusetts Institute of Technology. Department of Biological Engineering, Tharakaraman, Kannan, and Sasisekharan, Ram

Subjects
0301 basic medicine, medicine.drug_class, Protein domain, lcsh:Medicine, Complementarity determining region, Antigen-Antibody Complex, Dengue virus, Calorimetry, Cross Reactions, Molecular Dynamics Simulation, medicine.disease_cause, Monoclonal antibody, Antibodies, Monoclonal, Humanized, Serogroup, Epitope, Article, Dengue fever, Dengue, 03 medical and health sciences, Epitopes, Mice, Viral Envelope Proteins, Neutralization Tests, medicine, Animals, Humans, Amino Acid Sequence, lcsh:Science, Multidisciplinary, Binding Sites, biology, Chemistry, lcsh:R, Dengue Virus, Humanized Monoclonal Antibody 513, medicine.disease, Virology, 3. Good health, Protein Structure, Tertiary, 030104 developmental biology, Humanized mouse, biology.protein, lcsh:Q, Antibody, Sequence Alignment, Single-Chain Antibodies
Abstract

Dengue is a widespread viral disease with 3.6 billion people at risk worldwide. Humanized monoclonal antibody (mAb) 513, currently undergoing clinical trials in Singapore, targets an epitope on the envelope protein domain III exposed at the surface of the viral particle. This antibody potently neutralizes all four dengue virus serotypes in a humanized mouse model that recapitulates human dengue infection, without signs of antibody-mediated enhancement of the disease. The crystal structure of single-chain variable fragment (scFv) 513 bound to the envelope protein domain III from dengue virus serotype 4 was used as a template to explore the molecular origins of the broader cross-reactivity and increased in vivo potency of mAb 513, compared to the parent murine mAb 4E11, using molecular dynamics simulations and network analyses. These two methods are a powerful complement to existing structural and binding data and detail specific interactions that underpin the differential binding of the two antibodies. We found that a Glu at position H55 (GluH55) from the second Complementarity Determining Region of the Heavy chain (CDR-H2) which corresponds to Ala in 4E11, is a major contributor to the enhancement in the interactions of mAb 513 compared to 4E11. Importantly, we also validate the importance of GluH55using site-directed mutagenesis followed by isothermal titration calorimetry measurements., National Institutes of Health (U.S.) (Grant 1R01AI111395)

Published
2018

71. Macrocyclization of an all-D linear peptide improves target affinity and imparts cellular activity: A novel stapled α-helical peptide modality

Author

Kannan, Srinivasaraghavan, primary, Aronica, Pietro G. A., additional, Ng, Simon, additional, Thean, Dawn, additional, Frosi, Yuri, additional, Chee, Sharon, additional, Shimin, Jiang, additional, Yuen, Tsz Ying, additional, Sadruddin, Ahmad, additional, Kaan, Hung Yi Kristal, additional, Chandramohan, Arun, additional, Wong, Jin Huei, additional, Tan, Yaw Sing, additional, Ferrer, Fernando J., additional, Arumugam, Prakash, additional, Han, Yi, additional, Chen, Shiying, additional, Brown, Christopher J., additional, Johannes, Charles W., additional, Henry, Brian, additional, Lane, David P., additional, Sawyer, Tomi K., additional, Verma, Chandra S., additional, and Partridge, Anthony W., additional

Published
2019
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73. Incorporation of Putative Helix-Breaking Amino Acids in the Design of Novel Stapled Peptides: Exploring Biophysical and Cellular Permeability Properties

Author

Partridge, Anthony W., primary, Kaan, Hung Yi Kristal, additional, Juang, Yu-Chi, additional, Sadruddin, Ahmad, additional, Lim, Shuhui, additional, Brown, Christopher J., additional, Ng, Simon, additional, Thean, Dawn, additional, Ferrer, Fernando, additional, Johannes, Charles, additional, Yuen, Tsz Ying, additional, Kannan, Srinivasaraghavan, additional, Aronica, Pietro, additional, Tan, Yaw Sing, additional, Pradhan, Mohan R., additional, Verma, Chandra S., additional, Hochman, Jerome, additional, Chen, Shiying, additional, Wan, Hui, additional, Ha, Sookhee, additional, Sherborne, Brad, additional, Lane, David P., additional, and Sawyer, Tomi K., additional

Published
2019
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77. De-risking drug discovery of intracellular targeting peptides: screening strategies to eliminate false-positive hits

Author

Ng, Simon, primary, Juang, Yu-Chi, additional, Chandramohan, Arun, additional, Kristal Kaan, Hung Yi, additional, Sadruddin, Ahmad, additional, Yuen, Tsz Ying, additional, Ferrer, Fernando J., additional, Lee, Xue’Er Cheryl, additional, Xi, Liew, additional, Johannes, Charles W., additional, Brown, Christopher J., additional, Kannan, Srinivasaraghavan, additional, Aronica, Pietro G., additional, Berglund, Nils, additional, Verma, Chandra S., additional, Liu, Lijuan, additional, Stoeck, Alexander, additional, Sawyer, Tomi K., additional, Partridge, Anthony W., additional, and Lane, David P., additional

Published
2019
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79. Novel Inhibitors of the Calcium-Activated K+ Channel KCa3.1 to Treat Non-Alcoholic Fatty Liver Disease and Liver Fibrosis

Author

Theng Ong, Seow, primary, Thomas, Gemma, additional, Kannan, Srinivasaraghavan, additional, Her, Zhisheng, additional, Rui Ng, Xuan, additional, Chew, Xinying, additional, Nguyen, Hai M., additional, Wulff, Heike, additional, Verma, Chandra, additional, Chen, Qingfeng, additional, Ahmed, Mahmood, additional, and Chandy, K. George, additional

Published
2019
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81. TRK xDFG Mutations Trigger a Sensitivity Switch from Type I to II Kinase Inhibitors

Author

Cocco, Emiliano, primary, Lee, Ji Eun, additional, Kannan, Srinivasaraghavan, additional, Schram, Alison M., additional, Won, Helen, additional, Shifman, Sophie, additional, Kulick, Amanda, additional, Baldino, Laura, additional, Toska, Eneda, additional, Arena, Sabrina, additional, Mussolin, Benedetta, additional, Kannan, Ram, additional, Vasan, Neil, additional, Gorelick, Alexander N., additional, Berger, Michael F., additional, Liao, Yi, additional, Rix, Uwe, additional, Bardelli, Alberto, additional, Hechtman, Jacklyn, additional, de Stanchina, Elisa, additional, Hyman, David M., additional, Verma, Chandra, additional, Ventura, Andrea, additional, Drilon, Alexander, additional, and Scaltriti, Maurizio, additional

Published
2019
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82. Aspergillus fumigatus harbouring the sole Y121F mutation shows decreased susceptibility to voriconazole but maintained susceptibility to itraconazole and posaconazole

Author

Arnaud Fekkar, Annick Datry, Chandra S. Verma, K. Akshita, Kannan Srinivasaraghavan, M. Palous, Julien Lescar, I. Meyer, and Dominique Mazier

Subjects
Microbiology (medical), Posaconazole, Antifungal Agents, Itraconazole, Molecular Sequence Data, Mutation, Missense, medicine.disease_cause, Aspergillosis, Aspergillus fumigatus, Microbiology, Fungal Proteins, chemistry.chemical_compound, Cytochrome P-450 Enzyme System, Drug Resistance, Fungal, medicine, Pharmacology (medical), DNA, Fungal, Pharmacology, Voriconazole, chemistry.chemical_classification, Mutation, Ergosterol, biology, Sequence Analysis, DNA, Triazoles, biology.organism_classification, medicine.disease, Infectious Diseases, chemistry, Azole, medicine.drug
Abstract

Objectives Voriconazole, itraconazole and posaconazole are members of the azole family and widely used for the treatment of aspergillosis. They act by inhibiting the activity of the fungal Cyp51A enzyme. The emergence of environmental azole-resistant Aspergillus fumigatus strains raises major concerns for human health. Methods Recently, a new cyp51A-mediated resistance mechanism (namely TR46/Y121F/T289A) was described in clinical samples and patient-frequented environmental sites. In an azole-naive patient, we isolated an A. fumigatus strain that was not susceptible to voriconazole but was susceptible to itraconazole and posaconazole. Results A molecular analysis indicated a single Y121F substitution without the TR46 or T289A alterations, which to our knowledge has never been reported. Structure modelling and molecular dynamics offered an explanation for the resistance profile consistent with the structural differences between the three azoles. Conclusions Taken together, these observations suggest an original mechanism conferring resistance to azoles mediated by cyp51A of environmental origin. This uncommon susceptibility pattern might represent a 'missing link' between the wild-type A. fumigatus and the fully azole-resistant strain harbouring the TR46/Y121F/T289A mutations.

Published
2014
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84. Optimization of Selective Mitogen-Activated Protein Kinase Interacting Kinases 1 and 2 Inhibitors for the Treatment of Blast Crisis Leukemia

Author

Yang, Haiyan, primary, Chennamaneni, Lohitha Rao, additional, Ho, Melvyn Wai Tuck, additional, Ang, Shi Hua, additional, Tan, Eldwin Sum Wai, additional, Jeyaraj, Duraiswamy Athisayamani, additional, Yeap, Yoon Sheng, additional, Liu, Boping, additional, Ong, Esther Hq, additional, Joy, Joma Kanikadu, additional, Wee, John Liang Kuan, additional, Kwek, Perlyn, additional, Retna, Priya, additional, Dinie, Nurul, additional, Nguyen, Thuy Thi Hanh, additional, Tai, Shi Jing, additional, Manoharan, Vithya, additional, Pendharkar, Vishal, additional, Low, Choon Bing, additional, Chew, Yun Shan, additional, Vuddagiri, Susmitha, additional, Sangthongpitag, Kanda, additional, Choong, Meng Ling, additional, Lee, May Ann, additional, Kannan, Srinivasaraghavan, additional, Verma, Chandra S., additional, Poulsen, Anders, additional, Lim, Sharon, additional, Chuah, Charles, additional, Ong, Tiong Sin, additional, Hill, Jeffrey, additional, Matter, Alex, additional, and Nacro, Kassoum, additional

Published
2018
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85. A Novel Class of Schistosoma mansoni Histone Deacetylase 8 (HDAC8) Inhibitors Identified by Structure-Based Virtual Screening and In Vitro Testing

Author

Simoben, Conrad, primary, Robaa, Dina, additional, Chakrabarti, Alokta, additional, Schmidtkunz, Karin, additional, Marek, Martin, additional, Lancelot, Julien, additional, Kannan, Srinivasaraghavan, additional, Melesina, Jelena, additional, Shaik, Tajith, additional, Pierce, Raymond, additional, Romier, Christophe, additional, Jung, Manfred, additional, and Sippl, Wolfgang, additional

Published
2018
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87. Small Molecules Targeting the Inactive Form of the Mnk1/2 Kinases

Author

Kannan, Srinivasaraghavan, primary, Pradhan, Mohan R., additional, Cherian, Joseph, additional, Joseph, Thomas L., additional, Poh, Zhi Ying, additional, Hai Yan, Yang, additional, Melvyn, Ho, additional, Boping, Liu, additional, Jeffrey, Hill, additional, Nacro, Kassoum, additional, and Verma, Chandra S., additional

Published
2017
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88. Correction to Probing the Binding Mechanism of Mnk Inhibitors by Docking and Molecular Dynamics Simulations

Author

Kannan, Srinivasaraghavan, primary, Poulsen, Anders, additional, Yang, Hai Yan, additional, Ho, Melvyn, additional, Ang, Shi Hua, additional, Eldwin, Tan Sum Wai, additional, Jeyaraj, Duraiswamy Athisayamani, additional, Chennamaneni, Lohitha Rao, additional, Liu, Boping, additional, Hill, Jeffrey, additional, Verma, Chandra S., additional, and Nacro, Kassoum, additional

Published
2017
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94. Mechanisms of biased agonism by Gαi/o-biased stapled peptide agonists of the relaxin-3 receptor

Author

Jayakody, Tharindunee, Inoue, Asuka, Kannan, Srinivasaraghavan, Nakamura, Gaku, Kawakami, Kouki, Mendis, Krishan, Nguyen, Thanh-Binh, Li, Jianguo, Herr, Deron R., Verma, Chandra S., and Dawe, Gavin S.

Abstract

The neuropeptide relaxin-3 is composed of an A chain and a B chain held together by disulfide bonds, and it modulates functions such as anxiety and food intake by binding to and activating its cognate receptor RXFP3, mainly through the B chain. Biased ligands of RXFP3 would help to determine the molecular mechanisms underlying the activation of G proteins and β-arrestins downstream of RXFP3 that lead to such diverse functions. We showed that the i, i+4 stapled relaxin-3 B chains, 14s18 and d(1-7)14s18, were Gαi/o-biased agonists of RXFP3. These peptides did not induce recruitment of β-arrestin1/2 to RXFP3 by GPCR kinases (GRKs), in contrast to relaxin-3, which enabled the GRK2/3-mediated recruitment of β-arrestin1/2 to RXFP3. Relaxin-3 and the previously reported peptide 4 (an i, i+4 stapled relaxin-3 B chain) did not exhibit biased signaling. The staple linker of peptide 4 and parts of both the A chain and B chain of relaxin-3 interacted with extracellular loop 3 (ECL3) of RXFP3, moving it away from the binding pocket, suggesting that unbiased ligands promote a more open conformation of RXFP3. These findings highlight roles for the A chain and the N-terminal residues of the B chain of relaxin-3 in inducing conformational changes in RXFP3, which will help in designing selective biased ligands with improved therapeutic efficacy.

Published
2024
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96. Discovery of novel interacting partners of PSMD9, a proteasomal chaperone : role of an atypical and versatile PDZ-domain motif interaction and identification of putative functional modules

Author

Arun Kumar Somavarappu, Prasanna Venkatraman, Kannan Srinivasaraghavan, Indrajit Sahu, Ankita Desai, Chandra S. Verma, Nikhil Sangith, Spandana Medipally, and School of Biological Sciences

Subjects
Protein subunit, PDZ domain, RNA-binding protein, PSMD9, Computational biology, Article, General Biochemistry, Genetics and Molecular Biology, C-termini, Ribosomal protein, ELISA, enzyme linked immunosorbent assay, IL6 receptor, interleukin 6 receptor, PDZ, hnRNPA1, heterogeneous nuclear ribonucleoprotein A1, lcsh:QH301-705.5, Transcription factor, ComputingMethodologies_COMPUTERGRAPHICS, Genetics, Proteasome, biology, GH, growth hormone, Science::Biological sciences [DRNTU], lcsh:Biology (General), Chaperone (protein), Proteome, biology.protein, PSMD9, Proteasome Macropain non-ATPase subunit 9, Corrigendum
Abstract

Graphical abstract, Highlights • The structure and functions of PSMD9, a proteasomal chaperone, are uncharacterized. • PDZ-like domain of PSMD9 may recognize C-terminal residues in proteins. • Using conserved C-terminal motifs in human proteome, we identify novel binding partners. • hnRNPA1, GH, IL6-receptor, S14 and E12 interact with PSMD9 via a specific C-terminal motif. • We predict and confirm residues in the PDZ domain that are involved in this interaction., PSMD9 (Proteasome Macropain non-ATPase subunit 9), a proteasomal assembly chaperone, harbors an uncharacterized PDZ-like domain. Here we report the identification of five novel interacting partners of PSMD9 and provide the first glimpse at the structure of the PDZ-domain, including the molecular details of the interaction. We based our strategy on two propositions: (a) proteins with conserved C-termini may share common functions and (b) PDZ domains interact with C-terminal residues of proteins. Screening of C-terminal peptides followed by interactions using full-length recombinant proteins, we discovered hnRNPA1 (an RNA binding protein), S14 (a ribosomal protein), CSH1 (a growth hormone), E12 (a transcription factor) and IL6 receptor as novel PSMD9-interacting partners. Through multiple techniques and structural insights, we clearly demonstrate for the first time that human PDZ domain interacts with the predicted Short Linear Sequence Motif (SLIM) at the C-termini of the client proteins. These interactions are also recapitulated in mammalian cells. Together, these results are suggestive of the role of PSMD9 in transcriptional regulation, mRNA processing and editing, hormone and receptor activity and protein translation. Our proof-of-principle experiments endorse a novel and quick method for the identification of putative interacting partners of similar PDZ-domain proteins from the proteome and for discovering novel functions.

Published
2014

97. mAb806 binding to epidermal growth factor receptor: a computational study

Author

Ng, Yao Zong, Kannan, Srinivasaraghavan, Lane, David P., Fuentes, Gloria, Verma, Chandra Shekhar, and School of Biological Sciences

Subjects
EGFR, extracellular domain
Abstract

The epidermal growth factor receptor (EGFR) is an important target in the treatment of cancer. A very potent antibody, mAb806, has been developed against overexpressed EGFR and was found to be particularly active in brain tumors. Structural studies reveal that it binds to an epitope on the extracellular region of the EGFR. However, this epitope is cryptic/buried in crystal structures of the active (untethered) and inactive (tethered) EGFR, and it is unclear as to how the antibody interacts with this region. To explore this interaction, we combined molecular docking, steered molecular dynamics, and equilibrium molecular dynamics simulations. Our computational models reveal that the antibody induces local unfolding around the epitope to form the antibody–EGFR complex. In addition, regions in the vicinity of the epitope also modulate the interaction, which are in accordance with several other known antibody–antigen interactions, and offers new possibilities for the design of antibodies with increased potency and specificity for this receptor. ASTAR (Agency for Sci., Tech. and Research, S’pore)

Published
2014

99. PDK1-SGK1 Signaling Sustains AKT-Independent mTORC1 Activation and Confers Resistance to PI3Kα Inhibition

Author

Castel, Pau, primary, Ellis, Haley, additional, Bago, Ruzica, additional, Toska, Eneda, additional, Razavi, Pedram, additional, Carmona, F. Javier, additional, Kannan, Srinivasaraghavan, additional, Verma, Chandra S., additional, Dickler, Maura, additional, Chandarlapaty, Sarat, additional, Brogi, Edi, additional, Alessi, Dario R., additional, Baselga, José, additional, and Scaltriti, Maurizio, additional

Published
2016
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