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12 results on '"Thevakumaran, Neroshan"'

2. Dimeric Structure of Pseudokinase RNase L Bound to 2-5A Reveals a Basis for Interferon-Induced Antiviral Activity

Author

Huang, Hao, Zeqiraj, Elton, Dong, Beihua, Jha, Babal Kant, Duffy, Nicole M., Orlicky, Stephen, Thevakumaran, Neroshan, Talukdar, Manisha, Pillon, Monica C., Ceccarelli, Derek F., Wan, Leo C.K., Juang, Yu-Chi, Mao, Daniel Y.L., Gaughan, Christina, Brinton, Margo A., Perelygin, Andrey A., Kourinov, Igor, Guarné, Alba, Silverman, Robert H., and Sicheri, Frank

Published
2014
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4. MEK drives BRAF activation through allosteric control of KSR proteins

Author

Lavoie, Hugo, Sahmi, Malha, Maisonneuve, Pierre, Marullo, Sara A., Thevakumaran, Neroshan, Jin, Ting, Kurinov, Igor, Sicheri, Frank, and Therrien, Marc

Subjects
Research, Protein research, Extracellular signal-regulated kinases -- Research, Protein kinases -- Research, Allosteric enzymes -- Research
Abstract

Author(s): Hugo Lavoie [1]; Malha Sahmi [1]; Pierre Maisonneuve [2]; Sara A. Marullo [1]; Neroshan Thevakumaran [2, 3]; Ting Jin [1]; Igor Kurinov [4]; Frank Sicheri (corresponding author) [2, 3, [...]

Published
2018
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7. Genomic Discovery and Structure–Activity Exploration of a Novel Family of Enzyme-Activated Covalent Cyclin-Dependent Kinase Inhibitors

Author

Davison, Jack R., Hadjithomas, Michalis, Romeril, Stuart P., Choi, Yoon Jong, Bentley, Keith W., Biggins, John B., Chacko, Nadia, Castaldi, M. Paola, Chan, Lawrence K., Cumming, Jared N., Downes, Thomas D., Eisenhauer, Eric L., Fei, Fan, Fontaine, Benjamin M., Endalur Gopinarayanan, Venkatesh, Gurnani, Srishti, Hecht, Audrey, Hosford, Christopher J., Ibrahim, Ashraf, Jagels, Annika, Joubran, Camil, Kim, Ji-Nu, Lisher, John P., Liu, Daniel D., Lyles, James T., Mannara, Matteo N., Murray, Gordon J., Musial, Emilia, Niu, Mengyao, Olivares-Amaya, Roberto, Percuoco, Marielle, Saalau, Susanne, Sharpe, Kristen, Sheahan, Anjali V., Thevakumaran, Neroshan, Thompson, James E., Thompson, Dawn A., Wiest, Aric, Wyka, Stephen A., Yano, Jason, and Verdine, Gregory L.

Abstract

Fungi have historically been the source of numerous important medicinal compounds, but full exploitation of their genetic potential for drug development has been hampered in traditional discovery paradigms. Here we describe a radically different approach, top-down drug discovery (TD3), starting with a massive digital search through a database of over 100,000 fully genomicized fungi to identify loci encoding molecules with a predetermined human target. We exemplify TD3by the selection of cyclin-dependent kinases (CDKs) as targets and the discovery of two molecules, 1and 2, which inhibit therapeutically important human CDKs. 1and 2exhibit a remarkable mechanism, forming a site-selective covalent bond to the CDK active site Lys. We explored the structure–activity relationship via semi- and total synthesis, generating an analog, 43, with improved kinase selectivity, bioavailability, and efficacy. This work highlights the power of TD3to identify mechanistically and structurally novel molecules for the development of new medicines.

Published
2024
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9. Endogenous DNA replication stress results in expansion of dNTP pools and a mutator phenotype

Author

Davidson, Marta B., Katou, Yuki, Keszthelyi, Andrea, Sing, Tina L., Xia, Tian, Ou, Jiongwen, Vaisica, Jessica A., Thevakumaran, Neroshan, Marjavaara, Lisette, Myers, Chad L., Chabes, Andrei, Shirahige, Katsuhiko, Brown, Grant W., Davidson, Marta B., Katou, Yuki, Keszthelyi, Andrea, Sing, Tina L., Xia, Tian, Ou, Jiongwen, Vaisica, Jessica A., Thevakumaran, Neroshan, Marjavaara, Lisette, Myers, Chad L., Chabes, Andrei, Shirahige, Katsuhiko, and Brown, Grant W.

Abstract

The integrity of the genome depends on diverse pathways that regulate DNA metabolism. Defects in these pathways result in genome instability, a hallmark of cancer. Deletion of ELG1 in budding yeast, when combined with hypomorphic alleles of PCNA results in spontaneous DNA damage during S phase that elicits upregulation of ribonucleotide reductase (RNR) activity. Increased RNR activity leads to a dramatic expansion of deoxyribonucleotide (dNTP) pools in G1 that allows cells to synthesize significant fractions of the genome in the presence of hydroxyurea in the subsequent S phase. Consistent with the recognized correlation between dNTP levels and spontaneous mutation, compromising ELG1 and PCNA results in a significant increase in mutation rates. Deletion of distinct genome stability genes RAD54, RAD55, and TSA1 also results in increased dNTP levels and mutagenesis, suggesting that this is a general phenomenon. Together, our data point to a vicious circle in which mutations in gatekeeper genes give rise to genomic instability during S phase, inducing expansion of the dNTP pool, which in turn results in high levels of spontaneous mutagenesis. The EMBO Journal (2012) 31, 895-907. doi: 10.1038/emboj.2011.485; Published online 10 January 2012

Published
2012
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12. Crystal structure of a BRAF kinase domain monomer explains basis for allosteric regulation.

Author

Thevakumaran, Neroshan, Lavoie, Hugo, Critton, David A, Tebben, Andrew, Marinier, Anne, Sicheri, Frank, and Therrien, Marc

Subjects
*CRYSTAL structure, *ALLOSTERIC regulation, *CRYSTALLOGRAPHY, *PHYSIOLOGICAL control systems, *MONOMERS
Abstract

Reported RAF kinase domain structures adopt a side-to-side dimer configuration reflective of an 'on' state that underpins an allosteric mechanism of regulation. Atomic details of the monomer 'off' state have been elusive. Reinspection of the BRAF kinase domain structures revealed that sulfonamide inhibitors induce features of an off state, primarily a laterally displaced helix αC stabilized by the activation segment helix 1 (AS-H1). These features correlated with the ability of sulfonamides to disrupt human BRAF homodimers in cells, in vitro and in crystals yielding a structure of BRAF in a monomer state. The crystal structure revealed exaggerated, nonproductive positions of helix αC and AS-H1, the latter of which is the target of potent BRAF oncogenic mutations. Together, this work provides formal proof of an allosteric link between the RAF dimer interface, the activation segment and the catalytic infrastructure. [ABSTRACT FROM AUTHOR]

Published
2015
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