Research Summary

The long-term goals of our research are to understand how protein conformational ensembles are reshaped by perturbations, such as mutation and ligand binding, and to quantify how these perturbations impact protein function and organismal fitness. To accomplish these goals, we create new computational and biophysical approaches to study how proteins move between different conformational states. As a graduate student, with Tom Alber at UC Berkeley, James established room temperature X-ray data collection techniques and electron density sampling strategies to define protein conformational ensembles essential for catalysis. Prior to starting an independent position at UCSF, he was a visiting EMBO Short Term Fellow in the lab of Dan Tawfik at the Weizmann Institute of Science in Israel and developed expertise in directed evolution and high-throughput assays of enzymatic or binding activity. In 2011, James started his independent research career as a QB3 at UCSF Fellow and in 2013 was appointed as an Assistant Professor of Bioengineering and Therapeutic Sciences. At UCSF, his lab continue to pioneer new methods for extracting the maximal information from X-ray diffraction experiments and electron density maps. Additionally, the group uses two complementary approaches to study the relationship between protein conformational ensembles and function. To dissect consequences of mutations on organismal fitness, we use high-throughput systems biology and biophysical methods to analyze large sets of clinically or biophysically interesting mutations. To improve our ability to engineer new protein functions, we investigate changes to the conformational ensemble as new enzymatic and binding functions emerge from directed evolution studies.

Research Funding

  • July 1, 2020 - April 30, 2031 - Discovery of Novel Benzimidazole Resistance Mechanisms , Co-Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01AI153088
  • September 26, 2022 - August 31, 2027 - Discovering and Manipulating Macromolecular Conformational Ensembles , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R35GM145238
  • January 1, 2018 - December 31, 2021 - Resolving ensemble averaged conformations by multi-temperature x-ray crystallography , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01GM123159
  • September 20, 2011 - August 31, 2017 - The Impact of Mutation on the Conformations and Recognition of Ubiquitin , Principal Investigator . Sponsor: NIH, Sponsor Award ID: DP5OD009180
  • April 1, 2014 - March 31, 2017 - Model Comparison in Structural Biology , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R21GM110580

Education

2019 - Diversity, Equity, and Inclusion Champion Training, University of California
Ph.D., 2010 - Molecular and Cell Biology, University of California Berkeley
B.Sc., 2005 - Biology, McGill University

Honors & Awards

  • W.H. and W.L. Bragg Prize, International Union of Crystallography, 2020
  • Byers Award in Basic Science, UCSF, 2020
  • Packard Fellow, The David and Lucille Packard Foundation, 2014-2019
  • Searle Scholar, Kinship Foundation, 2014-2017
  • Pew Scholar in the Biomedical Sciences, Pew Charitable Trusts, 2014-2016

Selected Publications

  1. Fraser JS, Edgar S, Handly LN, Kosuri S, Chodera JD, Murcko M, Walters WP. Mapping the avoid-ome: a systematic open-science approach to predictive ADMET. Nat Commun. 2026 05 25; 17(1). View on PubMed
  2. Batra J, Rutkowska M, Zhou Y, Ye C, Adavikolanu R, Young JM, Anand D, Verma S, Parthasarathy H, Gordon M, Malpotra S, Cupic A, Kehrer T, Dos Santos M, Benjamin R, Moen JM, Winters DM, Caval V, Rojc A, Mena I, Aslam S, Martinez-Romero C, Viñas IC, Khalil Z, Farrugia K, Villalón-Letelier F, Banerjee A, Tussia-Cohen D, Diallo A, Maji S, Muralidharan M, Foussard H, Chen IP, Fuchs R, San Felipe CJ, Zuliani-Alvarez L, Choudhury P, Obernier K, Gracias S, Suryawanshi RK, Bonaventure B, Ibáñez C, Johnson JR, Juste J, Pache L, Stroud RM, Verba KA, Fraser JS, van Bakel H, Taha TY, Ott M, Hagai T, Jouvenet N, Demeret C, Polacco BJ, Swaney DL, Echeverria I, Bouhaddou M, Eckhardt M, Malik HS, Martinez-Sobrido L, Miorin L, García-Sastre A, Krogan NJ. Coronavirus protein interaction mapping in bat and human cells reveals network rewiring governing immune evasion and zoonotic potential. Cell Host Microbe. 2026 May 13. View on PubMed
  3. Lee IJ, Li Q, Raskar T, Pellegrino J, Ecker AK, Howard SY, Fraser JS, Seiple IB. Structure-based design and synthesis of group A streptogramins that bind to the nascent peptide exit tunnel of the ribosome. Eur J Med Chem. 2026 May 09; 316:118947. View on PubMed
  4. Chen Y, Bhattacharya S, Bergmann L, Correy GJ, Tan SK, Hou K, Biel JT, Lu L, Bakanas I, Gestwicki JE, Volkov AN, Korendovych IV, Polizzi NF, Fraser JS, DeGrado WF. Emergence of specific binding and catalysis from a designed generalist binding protein. Nat Chem. 2026 May 04. View on PubMed
  5. San Felipe CJ, Verba KA, Krogan NJ, Grabe M, Fraser JS. Inhibiting the interaction between the mitochondrial receptor Tom70 and SARS CoV 2 Orf9b with small molecules. bioRxiv. 2026 Apr 27. View on PubMed
  6. Bi Z, Chen YX, Young ID, Dandan MT, Joshi H, Su HW, Chen Y, Hong JY, Fraser JS, Javid B. Ribosomal RNA methylation by GidB modulates discrimination of mischarged tRNA. bioRxiv. 2026 Apr 23. View on PubMed
  7. MacDermott-Opeskin H, Scheen J, Wognum C, Horton JT, West D, Payne AM, Castellanos MA, Colby S, Griffen E, Cousins D, Stacey J, Reid L, Aschenbrenner JC, Fearon D, Balcomb B, Marples P, Tomlinson CWE, Lithgo R, Godoy AS, Winokan M, Barr H, Lahav N, Lavi M, Duberstein S, Cohen G, Fate G, Lefker B, Robinson R, Szommer T, Lynch N, Minh DDL, La VNT, Kang L, Huddleston K, Renslow R, Tollefson M, Walters WP, Xu C, Hsu J, St-Laurent J, Etsmoberg H, Zhu L, Quirke A, Abdul Haleem MI, Alibay I, Baid G, Birnbaum B, Bishop KP, Bohorquez H, Bose A, Brown CJ, Burns J, Cai L, Cedeno R, de Cesco S, Chupakhin V, Clark F, Cole DJ, Corbi-Verge C, Danial M, Davi A, Dehaen W, Doering NP, Dougha A, Dréanic MP, Eakin B, Ehrlich A, Elijosius R, Fülöp J, Gitter A, Goossens K, Gu Y, Head-Gordon T, Hoffer L, Hofmans J, Jiang E, Kaminow B, Khosravi S, Khoualdi AF, Lenselink EB, Liu Z, Liu Y, Liu S, Ma Y, Maher P, Mayer I, Mendez-Lucio O, Mey ASJS, Michel J, Montanari F, Niu T, Ogino R, Palaniappan A, Pan X, Patnaik A, Pham LH, Pinto L, Purnomo J, Rich A, Schaaf L, Schran C, Singh RK, Srilakshmi M, Srivastava SP, Sun K, Sun Z, Talagayev V, Thirukonda Subramanian Balakrishnan B, Titus I, Tkatchenko A, Treyde W, Tricarico G, Tripp A, Vithayapalert N, Wang Y, Wasi AT, Wedig S, Wolber G, Xu B, Zhou W, von Delft F, Lee A, Kirkegaard K, Sjö P, Fraser JS, Chodera JD. A Computational Community Blind Challenge on Pan-Coronavirus Drug Discovery Data. J Chem Inf Model. 2026 Mar 23; 66(6):3129-3149. View on PubMed
  8. Kleinman JI, Raskar T, Klepacki D, Szal T, Vázquez-Laslop N, Mankin AS, Fraser JS, Fujimori DG. Structural modification of oxazolidinone antibiotics alters nascent peptide stalling preference and peptide trajectory through the ribosome. bioRxiv. 2026 Feb 18. View on PubMed
  9. Chodera JD, Walters WP, Kosuri S, Fraser JS. Blind Challenges Let Us See the Path Forward for Predictive Models. J Chem Inf Model. 2026 Feb 23; 66(4):1947-1949. View on PubMed
  10. Herasymenko O, Silva M, Correy GJ, Abu-Saleh AAA, Ackloo S, Arrowsmith C, Ashworth A, Ban F, Beck H, Bishop KP, Bohórquez HJ, Bolotokova A, Breznik M, Chau I, Chen Y, Cherkasov A, Dehaen W, Della Corte D, Denzinger K, Doering NP, Edfeldt K, Edwards A, Fayne D, Gentile F, Gibson E, Gokdemir O, Gunnarsson A, Günther J, Irwin JJ, Jensen JH, Harding RJ, Hillisch A, Hoffer L, Hogner A, Hutchinson A, Kandwal S, Karlova A, Koirala K, Kotelnikov S, Kozakov D, Lee J, Lee S, Lessel U, Liu S, Liu X, Loppnau P, Meiler J, Moretti R, Moroz YS, Muvva C, Oprea TI, Paige B, Pandit A, Park K, Poda G, Protopopov MV, Pütter V, Ravichandran R, Rognan D, Rosta E, Sabnis Y, Scott T, Seitova A, Sharma P, Sindt F, Song M, Steinmann C, Stevens R, Talagayev V, Tararina VV, Tarkhanova O, Tingey D, Trant JF, Treleaven D, Tropsha A, Walters P, Wells J, Westermaier Y, Wolber G, Wortmann L, Zheng S, Fraser JS, Schapira M. CACHE Challenge #3: Targeting the Nsp3 Macrodomain of SARS-CoV-2. J Chem Inf Model. 2026 Feb 09; 66(3):1566-1581. View on PubMed
  11. Seo L, Farran I, Aslam A, Li X, Jaishankar P, Ashworth A, Fraser JS, Renslo AR, Wankowicz SA. Crystallographic Ensembles Reveal the Structural Basis of Binding Entropy in SARS-CoV2 Macrodomain. bioRxiv. 2025 Dec 23. View on PubMed
  12. Jaishankar P, Correy GJ, Matsui Y, Togo T, Rachman MM, Stevens MGV, Hantz ER, Zheng J, Diolaiti ME, Montano M, Taha TY, Rosecrans J, Pampel J, Krogan NJ, Shoichet BK, Ashworth A, Ott M, Fraser JS, Renslo AR. Discovery of AVI-6451, a Potent and Selective Inhibitor of the SARS-CoV-2 ADP-Ribosylhydrolase Mac1 with Oral Efficacy In Vivo. J Med Chem. 2026 Jan 08; 69(1):553-573. View on PubMed
  13. Linossi EM, Espinoza CA, Estevam GO, Fraser JS, Jura N. Autoregulation of the MET receptor tyrosine kinase by its intracellular juxtamembrane domain. Biochem J. 2025 12 11; 482(24). View on PubMed
  14. Rahul K Suryawanshi, Priyadarshini Jaishankar, Galen J Correy, Moira M Rachman, Patrick C O'Leary, Taha Y Taha, Yusuke Matsui, Francisco J Zapatero-Belinchón, Maria McCavitt-Malvido, Yagmur U Doruk, Maisie GV Stevens, Morgan E Diolaiti, Manasi P Jogalekar, Huadong Chen, Alicia L Richards, Pornparn Kongpracha, Sofia Bali, Mauricio Montano, Julia Rosecrans, Michael Matthay, Takaya Togo, Ryan L Gonciarz, Saumya Gopalkrishnan, R Jeffrey Neitz, Nevan J Krogan, Danielle L Swaney, Brian K Shoichet, Melanie Ott, Adam R Renslo, Alan Ashworth, James S Fraser. The Mac1 ADP-ribosylhydrolase is a therapeutic target for SARS-CoV-2. eLife. 2025 Nov 19; 14. View on PubMed
  15. Suryawanshi RK, Jaishankar P, Correy GJ, Rachman MM, O'Leary PC, Taha TY, Matsui Y, Zapatero-Belinchón FJ, McCavitt-Malvido M, Doruk YU, Stevens MGV, Diolaiti ME, Jogalekar MP, Chen H, Richards AL, Kongpracha P, Bali S, Montano M, Rosecrans J, Matthay M, Togo T, Gonciarz RL, Gopalkrishnan S, Neitz RJ, Krogan NJ, Swaney DL, Shoichet BK, Ott M, Renslo AR, Ashworth A, Fraser JS. The Mac1 ADP-ribosylhydrolase is a therapeutic target for SARS-CoV-2. Elife. 2025 Nov 19; 14. View on PubMed
  16. Jaishankar P, Correy GJ, Matsui Y, Togo T, Rachman MM, Stevens MGV, Hantz ER, Zheng J, Diolaiti ME, Montano M, Taha TY, Rosecrans J, Pampel J, Krogan NJ, Shoichet BK, Ashworth A, Ott M, Fraser JS, Renslo AR. Discovery of AVI-6451, a Potent and Selective Inhibitor of the SARS-CoV-2 ADP-Ribosylhydrolase Mac1 with Oral Efficacy in vivo. bioRxiv. 2025 Oct 14. View on PubMed
  17. Bardossy ES, Bergmann L, Henrion-Lacritick A, Nigg J, Correy GJ, Ashworth A, Fraser JS, Saleh MC. Macrodomain ADP-ribose binding but not ADP-ribosylhydrolase activity is critical for chikungunya virus infection of Aedes mosquitoes. bioRxiv. 2025 Oct 09. View on PubMed
  18. Hancock M, Holton J, Fraser JS, Adams PD, Sali A. Bayesian multi-state multi-condition modeling of a protein structure based on X-ray crystallography data. bioRxiv. 2025 Oct 07. View on PubMed
  19. Suryawanshi RK, Jaishankar P, Correy GJ, Rachman MM, O'Leary PC, Taha TY, Matsui Y, Zapatero-Belinchón FJ, McCavitt-Malvido M, Doruk YU, Stevens MGV, Diolaiti ME, Jogalekar MP, Chen H, Richards AL, Kongpracha P, Bali S, Montano M, Rosecrans J, Matthay M, Togo T, Gonciarz RL, Gopalkrishnan S, Neitz RJ, Krogan NJ, Swaney DL, Shoichet BK, Ott M, Renslo AR, Ashworth A, Fraser JS. The Mac1 ADP-ribosylhydrolase is a Therapeutic Target for SARS-CoV-2. bioRxiv. 2025 Oct 06. View on PubMed
  20. Zarifi N, Asthana P, Doustmohammadi H, Klaus C, Sanchez J, Hunt SE, Rakotoharisoa RV, Osuna S, Fraser JS, Chica RA. Distal mutations enhance catalysis in designed enzymes by facilitating substrate binding and product release. Nat Commun. 2025 Sep 30; 16(1):8662. View on PubMed

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