James Fraser, PhD

Associate Professor
Bioengineering
+1 415 493-8421

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.

Publications: 

Extending chemical perturbations of the ubiquitin fitness landscape in a classroom setting reveals new constraints on sequence tolerance.

Biology open

Mavor D, Barlow KA, Asarnow D, Birman Y, Britain D, Chen W, Green EM, Kenner LR, Mensa B, Morinishi LS, Nelson CA, Poss EM, Suresh P, Tian R, Arhar T, Ary BE, Bauer DP, Bergman ID, Brunetti RM, Chio CM, Dai SA, Dickinson MS, Elledge SK, Helsell CVM, Hendel NL, Kang E, Kern N, Khoroshkin MS, Kirkemo LL, Lewis GR, Lou K, Marin WM, Maxwell AM, McTigue PF, Myers-Turnbull D, Nagy TL, Natale AM, Oltion K, Pourmal S, Reder GK, Rettko NJ, Rohweder PJ, Schwarz DMC, Tan SK, Thomas PV, Tibble RW, Town JP, Tsai MK, Ugur FS, Wassarman DR, Wolff AM, Wu TS, Bogdanoff D, Li J, Thorn KS, O'Conchúir S, Swaney DL, Chow ED, Madhani HD, Redding S, Bolon DN, Kortemme T, DeRisi JL, Kampmann M, Fraser JS

An expanded allosteric network in PTP1B by multitemperature crystallography, fragment screening, and covalent tethering.

eLife

Keedy DA, Hill ZB, Biel JT, Kang E, Rettenmaier TJ, Brandao-Neto J, Pearce NM, von Delft F, Wells JA, Fraser JS

Rescue of conformational dynamics in enzyme catalysis by directed evolution.

Nature communications

Otten R, Liu L, Kenner LR, Clarkson MW, Mavor D, Tawfik DS, Kern D, Fraser JS

Bringing diffuse X-ray scattering into focus.

Current opinion in structural biology

Wall ME, Wolff AM, Fraser JS

XFEL structures of the influenza M2 proton channel: Room temperature water networks and insights into proton conduction.

Proceedings of the National Academy of Sciences of the United States of America

Thomaston JL, Woldeyes RA, Nakane T, Yamashita A, Tanaka T, Koiwai K, Brewster AS, Barad BA, Chen Y, Lemmin T, Uervirojnangkoorn M, Arima T, Kobayashi J, Masuda T, Suzuki M, Sugahara M, Sauter NK, Tanaka R, Nureki O, Tono K, Joti Y, Nango E, Iwata S, Yumoto F, Fraser JS, DeGrado WF

Allosteric Inhibitors, Crystallography, and Comparative Analysis Reveal Network of Coordinated Movement across Human Herpesvirus Proteases.

Journal of the American Chemical Society

Acker TM, Gable JE, Bohn MF, Jaishankar P, Thompson MC, Fraser JS, Renslo AR, Craik CS

Hydrogen-Deuterium Exchange of Lipoxygenase Uncovers a Relationship between Distal, Solvent Exposed Protein Motions and the Thermal Activation Barrier for Catalytic Proton-Coupled Electron Tunneling.

ACS central science

Offenbacher AR, Hu S, Poss EM, Carr CAM, Scouras AD, Prigozhin DM, Iavarone AT, Palla A, Alber T, Fraser JS, Klinman JP

Flexibility and Design: Conformational Heterogeneity along the Evolutionary Trajectory of a Redesigned Ubiquitin.

Structure (London, England : 1993)

Biel JT, Thompson MC, Cunningham CN, Corn JE, Fraser JS

Cytidine deaminase efficiency of the lentiviral viral restriction factor APOBEC3C correlates with dimerization.

Nucleic acids research

Adolph MB, Ara A, Feng Y, Wittkopp CJ, Emerman M, Fraser JS, Chelico L

Conformational variation of proteins at room temperature is not dominated by radiation damage.

Journal of synchrotron radiation

Russi S, González A, Kenner LR, Keedy DA, Fraser JS, van den Bedem H

Automated structure refinement of macromolecular assemblies from cryo-EM maps using Rosetta.

eLife

Wang RY, Song Y, Barad BA, Cheng Y, Fraser JS, DiMaio F

From deep TLS validation to ensembles of atomic models built from elemental motions. Addenda and corrigendum.

Acta crystallographica. Section D, Structural biology

Urzhumtsev A, Afonine PV, Van Benschoten AH, Fraser JS, Adams PD

SCIENTIFIC COMMUNITY. Preprints for the life sciences.

Science (New York, N.Y.)

Berg JM, Bhalla N, Bourne PE, Chalfie M, Drubin DG, Fraser JS, Greider CW, Hendricks M, Jones C, Kiley R, King S, Kirschner MW, Krumholz HM, Lehmann R, Leptin M, Pulverer B, Rosenzweig B, Spiro JE, Stebbins M, Strasser C, Swaminathan S, Turner P, Vale RD, VijayRaghavan K, Wolberger C

Determination of ubiquitin fitness landscapes under different chemical stresses in a classroom setting.

eLife

Mavor D, Barlow K, Thompson S, Barad BA, Bonny AR, Cario CL, Gaskins G, Liu Z, Deming L, Axen SD, Caceres E, Chen W, Cuesta A, Gate RE, Green EM, Hulce KR, Ji W, Kenner LR, Mensa B, Morinishi LS, Moss SM, Mravic M, Muir RK, Niekamp S, Nnadi CI, Palovcak E, Poss EM, Ross TD, Salcedo EC, See SK, Subramaniam M, Wong AW, Li J, Thorn KS, Conchúir SÓ, Roscoe BP, Chow ED, DeRisi JL, Kortemme T, Bolon DN, Fraser JS

Measuring and modeling diffuse scattering in protein X-ray crystallography.

Proceedings of the National Academy of Sciences of the United States of America

Van Benschoten AH, Liu L, Gonzalez A, Brewster AS, Sauter NK, Fraser JS, Wall ME

Data publication with the structural biology data grid supports live analysis.

Nature communications

Meyer PA, Socias S, Key J, Ransey E, Tjon EC, Buschiazzo A, Lei M, Botka C, Withrow J, Neau D, Rajashankar K, Anderson KS, Baxter RH, Blacklow SC, Boggon TJ, Bonvin AM, Borek D, Brett TJ, Caflisch A, Chang CI, Chazin WJ, Corbett KD, Cosgrove MS, Crosson S, Dhe-Paganon S, Di Cera E, Drennan CL, Eck MJ, Eichman BF, Fan QR, Ferré-D'Amaré AR, Fromme JC, Garcia KC, Gaudet R, Gong P, Harrison SC, Heldwein EE, Jia Z, Keenan RJ, Kruse AC, Kvansakul M, McLellan JS, Modis Y, Nam Y, Otwinowski Z, Pai EF, Pereira PJ, Petosa C, Raman CS, Rapoport TA, Roll-Mecak A, Rosen MK, Rudenko G, Schlessinger J, Schwartz TU, Shamoo Y, Sondermann H, Tao YJ, Tolia NH, Tsodikov OV, Westover KD, Wu H, Foster I, Fraser JS, Maia FR, Gonen T, Kirchhausen T, Diederichs K, Crosas M, Sliz P

CryptoSite: Expanding the Druggable Proteome by Characterization and Prediction of Cryptic Binding Sites.

Journal of molecular biology

Cimermancic P, Weinkam P, Rettenmaier TJ, Bichmann L, Keedy DA, Woldeyes RA, Schneidman-Duhovny D, Demerdash ON, Mitchell JC, Wells JA, Fraser JS, Sali A

High-density grids for efficient data collection from multiple crystals.

Acta crystallographica. Section D, Structural biology

Baxter EL, Aguila L, Alonso-Mori R, Barnes CO, Bonagura CA, Brehmer W, Brunger AT, Calero G, Caradoc-Davies TT, Chatterjee R, Degrado WF, Fraser JS, Ibrahim M, Kern J, Kobilka BK, Kruse AC, Larsson KM, Lemke HT, Lyubimov AY, Manglik A, McPhillips SE, Norgren E, Pang SS, Soltis SM, Song J, Thomaston J, Tsai Y, Weis WI, Woldeyes RA, Yachandra V, Yano J, Zouni A, Cohen AE

High-resolution structures of the M2 channel from influenza A virus reveal dynamic pathways for proton stabilization and transduction.

Proceedings of the National Academy of Sciences of the United States of America

Thomaston JL, Alfonso-Prieto M, Woldeyes RA, Fraser JS, Klein ML, Fiorin G, DeGrado WF

Exposing Hidden Alternative Backbone Conformations in X-ray Crystallography Using qFit.

PLoS computational biology

Keedy DA, Fraser JS, van den Bedem H

Mapping the conformational landscape of a dynamic enzyme by multitemperature and XFEL crystallography.

eLife

Keedy DA, Kenner LR, Warkentin M, Woldeyes RA, Hopkins JB, Thompson MC, Brewster AS, Van Benschoten AH, Baxter EL, Uervirojnangkoorn M, McPhillips SE, Song J, Alonso-Mori R, Holton JM, Weis WI, Brunger AT, Soltis SM, Lemke H, Gonzalez A, Sauter NK, Cohen AE, van den Bedem H, Thorne RE, Fraser JS

EMRinger: side chain-directed model and map validation for 3D cryo-electron microscopy.

Nature methods

Barad BA, Echols N, Wang RY, Cheng Y, DiMaio F, Adams PD, Fraser JS

From deep TLS validation to ensembles of atomic models built from elemental motions.

Acta crystallographica. Section D, Biological crystallography

Urzhumtsev A, Afonine PV, Van Benschoten AH, Fraser JS, Adams PD

Predicting X-ray diffuse scattering from translation-libration-screw structural ensembles.

Acta crystallographica. Section D, Biological crystallography

Van Benschoten AH, Afonine PV, Terwilliger TC, Wall ME, Jackson CJ, Sauter NK, Adams PD, Urzhumtsev A, Fraser JS

One Crystal, Two Temperatures: Cryocooling Penalties Alter Ligand Binding to Transient Protein Sites.

Chembiochem : a European journal of chemical biology

Fischer M, Shoichet BK, Fraser JS

Negative Epistasis and Evolvability in TEM-1 ß-Lactamase--The Thin Line between an Enzyme's Conformational Freedom and Disorder.

Journal of molecular biology

Dellus-Gur E, Elias M, Caselli E, Prati F, Salverda ML, de Visser JA, Fraser JS, Tawfik DS

Lineage-Specific Viral Hijacking of Non-canonical E3 Ubiquitin Ligase Cofactors in the Evolution of Vif Anti-APOBEC3 Activity.

Cell reports

Kane JR, Stanley DJ, Hultquist JF, Johnson JR, Mietrach N, Binning JM, Jónsson SR, Barelier S, Newton BW, Johnson TL, Franks-Skiba KE, Li M, Brown WL, Gunnarsson HI, Adalbjornsdóttir A, Fraser JS, Harris RS, Andrésdóttir V, Gross JD, Krogan NJ

Keep on moving: discovering and perturbing the conformational dynamics of enzymes.

Accounts of chemical research

Bhabha G, Biel JT, Fraser JS

Conformational dynamics of a crystalline protein from microsecond-scale molecular dynamics simulations and diffuse X-ray scattering.

Proceedings of the National Academy of Sciences of the United States of America

Wall ME, Van Benschoten AH, Sauter NK, Adams PD, Fraser JS, Terwilliger TC

Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine.

Cell host & microbe

Williams BB, Van Benschoten AH, Cimermancic P, Donia MS, Zimmermann M, Taketani M, Ishihara A, Kashyap PC, Fraser JS, Fischbach MA

E pluribus unum, no more: from one crystal, many conformations.

Current opinion in structural biology

Woldeyes RA, Sivak DA, Fraser JS

Crystal cryocooling distorts conformational heterogeneity in a model Michaelis complex of DHFR.

Structure (London, England : 1993)

Keedy DA, van den Bedem H, Sivak DA, Petsko GA, Ringe D, Wilson MA, Fraser JS

Diffuse X-ray scattering to model protein motions.

Structure (London, England : 1993)

Wall ME, Adams PD, Fraser JS, Sauter NK

Integrated description of protein dynamics from room-temperature X-ray crystallography and NMR.

Proceedings of the National Academy of Sciences of the United States of America

Fenwick RB, van den Bedem H, Fraser JS, Wright PE

Protein structural ensembles are revealed by redefining X-ray electron density noise.

Proceedings of the National Academy of Sciences of the United States of America

Lang PT, Holton JM, Fraser JS, Alber T

From structure to systems: high-resolution, quantitative genetic analysis of RNA polymerase II.

Cell

Braberg H, Jin H, Moehle EA, Chan YA, Wang S, Shales M, Benschop JJ, Morris JH, Qiu C, Hu F, Tang LK, Fraser JS, Holstege FC, Hieter P, Guthrie C, Kaplan CD, Krogan NJ

Automated identification of functional dynamic contact networks from X-ray crystallography.

Nature methods

van den Bedem H, Bhabha G, Yang K, Wright PE, Fraser JS

From systems to structure: bridging networks and mechanism.

Molecular cell

Fraser JS, Gross JD, Krogan NJ

Flexible backbone sampling methods to model and design protein alternative conformations.

Methods in enzymology

Ollikainen N, Smith CA, Fraser JS, Kortemme T

CheShift-2 resolves a local inconsistency between two X-ray crystal structures.

Journal of biomolecular NMR

Vila JA, Sue SC, Fraser JS, Scheraga HA, Dyson HJ

Systematic functional prioritization of protein posttranslational modifications.

Cell

Beltrao P, Albanèse V, Kenner LR, Swaney DL, Burlingame A, Villén J, Lim WA, Fraser JS, Frydman J, Krogan NJ

Control of protein signaling using a computationally designed GTPase/GEF orthogonal pair.

Proceedings of the National Academy of Sciences of the United States of America

Kapp GT, Liu S, Stein A, Wong DT, Reményi A, Yeh BJ, Fraser JS, Taunton J, Lim WA, Kortemme T

Accessing protein conformational ensembles using room-temperature X-ray crystallography.

Proceedings of the National Academy of Sciences of the United States of America

Fraser JS, van den Bedem H, Samelson AJ, Lang PT, Holton JM, Echols N, Alber T

Mining electron density for functionally relevant protein polysterism in crystal structures.

Cellular and molecular life sciences : CMLS

Fraser JS, Jackson CJ

The tumor-associated EpCAM regulates morphogenetic movements through intracellular signaling.

The Journal of cell biology

Maghzal N, Vogt E, Reintsch W, Fraser JS, Fagotto F

Automated electron-density sampling reveals widespread conformational polymorphism in proteins.

Protein science : a publication of the Protein Society

Lang PT, Ng HL, Fraser JS, Corn JE, Echols N, Sales M, Holton JM, Alber T

Hidden alternative structures of proline isomerase essential for catalysis.

Nature

Fraser JS, Clarkson MW, Degnan SC, Erion R, Kern D, Alber T

Immunoglobulin-like domains on bacteriophage: weapons of modest damage?

Current opinion in microbiology

Fraser JS, Maxwell KL, Davidson AR

An atypical receiver domain controls the dynamic polar localization of the Myxococcus xanthus social motility protein FrzS.

Molecular microbiology

Fraser JS, Merlie JP, Echols N, Weisfield SR, Mignot T, Wemmer DE, Zusman DR, Alber T

Ig-like domains on bacteriophages: a tale of promiscuity and deceit.

Journal of molecular biology

Fraser JS, Yu Z, Maxwell KL, Davidson AR