Research Summary

Three main foci characterize my research. First, we aim to understand transport, cellular signaling and communication across cell membranes at the molecular level. Most recently this includes the first structures of channels in endolysosomes (TPCs) that participate in regulating nutrient acquisition. This gave us the first structure of any resting state voltage sensor, because its voltage sensitivity is tuned by lumenal calcium ions that lead to a ~1% open probability at 0 volts potential across the membrane. Most recently we removed this regulatory site, changing the open probability to ~99% at 0 volts. This gave us the first case of any voltage sensor seen in resting, and in active state in the same voltage gated ion channel. TPCs are critical to Ebola viral fusion and entry via the endolysosome; the structure is bound to an inhibitor NED19 that cures infected mice of Ebola. Another aim is on packaging of neurotransmitters into synaptic vesicles. The second focus is on understanding how macromolecular structure encodes specificity and affinity, at protein - protein and at protein - ligand interfaces, and how this can be used for biotherapeutics and drug design. To these ends we have determined the high-resolution three-dimensional atomic structures of over 330 proteins in many different classes, and used these structures to help define biological, biochemical, and cellular function, and as templates for drug design. We seek to determine the structures of membrane receptors, channels and transporters using X-ray and cryo electron microscopy. We address the cellular partners of HIV proteins in attempts to elucidate novel drug targets for anti-HIV therapy. We also address recently identified essential enzymes and transporters of mycobacterium tuberculosis, and P.falciparum as targets for drug discovery. The third area of focus concerns RNA-protein recognition, specificity and modification. We described and decoded several methylases, pseudouridine synthases showing how they achieve specificity by allosteric alteration of RNA. The most recent of these is the RNA methylase that tailors Lys3 tRNA by methylating the base A58; bases 58-72 act as the primer for HIV reverse transcription. Knockout of this enzyme reduces HIV viral infectivity by ~50%.

Research Funding

  • April 1, 1979 - December 31, 2024 - Molecular Basis for Transmembrane Conduction & Signaling , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01GM024485
  • August 1, 2015 - April 30, 2024 - Structural Basis of Vesicular Neurotransmitter Transport , Co-Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01NS089713
  • August 27, 2007 - August 31, 2022 - HARC Center: HIV Accessory and Regulatory Complexes , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P50GM082250
  • August 1, 2015 - July 31, 2020 - Mapping the conformational cycle of transmembrane transporters , Principal Investigator . Sponsor: NIH, Sponsor Award ID: P01GM111126

Education

Clare College, U. of Cambridge, U.K., B.A., 1964, Natural Sciences
Clare College, U. of Cambridge, U.K., M.A., 1968, Natural Sciences
Birkbeck College, London University, U.K., Ph.D., 1968, Biological Crystallography
California Institute of Technology, Los Angeles, CA, Postdoctoral Fellow, Chemistry

Honors & Awards

  • 1992-present
    FRSM Fellow of the Royal Society of Medicine (United Kingdom)
  • 1995-present
    Fellow of the New York Academy of Sciences
  • 1999-present
    Founding Fellow of the Biophysical Society of the United States
  • 2003-present
    NAS Elected Member of the National Academies of Science (NAS)
  • 2007
    Fellow of the American Academy of Arts and Sciences
  • 2008
    Hans Neurath Award of the Protein Society US
  • 2009
    Anatrace Award of the Biophysical Society US
  • 2006-2016
    NIH Merit Award
  • 2018
    The 2018 UCSF Lecture in Basic Science [details]
  • 2019
    The Keynote, 29th Annual Conference of the World Molecular Engineering Network, Cabo San Lucas Mexico

Selected Publications

  1. Dickinson MS, Lu J, Gupta M, Marten I, Hedrich R, Stroud RM. Molecular basis of multistep voltage activation in plant two-pore channel 1. Proc Natl Acad Sci U S A. 2022 03 01; 119(9).  View on PubMed
  2. Dickinson MS, Pourmal S, Gupta M, Bi M, Stroud RM. Symmetry Reduction in a Hyperpolarization-Activated Homotetrameric Ion Channel. Biochemistry. 2021 Dec 29.  View on PubMed
  3. Eriksen J, Li F, Stroud RM, Edwards RH. Allosteric Inhibition of a Vesicular Glutamate Transporter by an Isoform-Specific Antibody. Biochemistry. 2021 08 17; 60(32):2463-2470.  View on PubMed
  4. Liu Y, Li C, Gupta M, Verma N, Johri AK, Stroud RM, Voth GA. Key computational findings reveal proton transfer as driving the functional cycle in the phosphate transporter PiPT. Proc Natl Acad Sci U S A. 2021 06 22; 118(25).  View on PubMed
  5. Gupta M, Azumaya CM, Moritz M, Pourmal S, Diallo A, Merz GE, Jang G, Bouhaddou M, Fossati A, Brilot AF, Diwanji D, Hernandez E, Herrera N, Kratochvil HT, Lam VL, Li F, Li Y, Nguyen HC, Nowotny C, Owens TW, Peters JK, Rizo AN, Schulze-Gahmen U, Smith AM, Young ID, Yu Z, Asarnow D, Billesbølle C, Campbell MG, Chen J, Chen KH, Chio US, Dickinson MS, Doan L, Jin M, Kim K, Li J, Li YL, Linossi E, Liu Y, Lo M, Lopez J, Lopez KE, Mancino A, Moss FR, Paul MD, Pawar KI, Pelin A, Pospiech TH, Puchades C, Remesh SG, Safari M, Schaefer K, Sun M, Tabios MC, Thwin AC, Titus EW, Trenker R, Tse E, Tsui TKM, Wang F, Zhang K, Zhang Y, Zhao J, Zhou F, Zhou Y, Zuliani-Alvarez L, QCRG Structural Biology Consortium, Agard DA, Cheng Y, Fraser JS, Jura N, Kortemme T, Manglik A, Southworth DR, Stroud RM, Swaney DL, Krogan NJ, Frost A, Rosenberg OS, Verba KA. CryoEM and AI reveal a structure of SARS-CoV-2 Nsp2, a multifunctional protein involved in key host processes. bioRxiv. 2021 May 11.  View on PubMed
  6. Vecchio AJ, Rathnayake SS, Stroud RM. Structural basis for Clostridium perfringens enterotoxin targeting of claudins at tight junctions in mammalian gut. Proc Natl Acad Sci U S A. 2021 04 13; 118(15).  View on PubMed
  7. Kholodar SA, Finer-Moore JS, Swiderek K, Arafet K, Moliner V, Stroud RM, Kohen A. Caught in Action: X-ray Structure of Thymidylate Synthase with Noncovalent Intermediate Analog. Biochemistry. 2021 04 27; 60(16):1243-1247.  View on PubMed
  8. Li F, Egea PF, Vecchio AJ, Asial I, Gupta M, Paulino J, Bajaj R, Dickinson MS, Ferguson-Miller S, Monk BC, Stroud RM. Highlighting membrane protein structure and function: A celebration of the Protein Data Bank. J Biol Chem. 2021 Jan-Jun; 296:100557.  View on PubMed
  9. Miller-Vedam LE, Bräuning B, Popova KD, Schirle Oakdale NT, Bonnar JL, Prabu JR, Boydston EA, Sevillano N, Shurtleff MJ, Stroud RM, Craik CS, Schulman BA, Frost A, Weissman JS. Structural and mechanistic basis of the EMC-dependent biogenesis of distinct transmembrane clients. Elife. 2020 11 25; 9.  View on PubMed
  10. Gordon DE, Hiatt J, Bouhaddou M, Rezelj VV, Ulferts S, Braberg H, Jureka AS, Obernier K, Guo JZ, Batra J, Kaake RM, Weckstein AR, Owens TW, Gupta M, Pourmal S, Titus EW, Cakir M, Soucheray M, McGregor M, Cakir Z, Jang G, O'Meara MJ, Tummino TA, Zhang Z, Foussard H, Rojc A, Zhou Y, Kuchenov D, Hüttenhain R, Xu J, Eckhardt M, Swaney DL, Fabius JM, Ummadi M, Tutuncuoglu B, Rathore U, Modak M, Haas P, Haas KM, Naing ZZC, Pulido EH, Shi Y, Barrio-Hernandez I, Memon D, Petsalaki E, Dunham A, Marrero MC, Burke D, Koh C, Vallet T, Silvas JA, Azumaya CM, Billesbølle C, Brilot AF, Campbell MG, Diallo A, Dickinson MS, Diwanji D, Herrera N, Hoppe N, Kratochvil HT, Liu Y, Merz GE, Moritz M, Nguyen HC, Nowotny C, Puchades C, Rizo AN, Schulze-Gahmen U, Smith AM, Sun M, Young ID, Zhao J, Asarnow D, Biel J, Bowen A, Braxton JR, Chen J, Chio CM, Chio US, Deshpande I, Doan L, Faust B, Flores S, Jin M, Kim K, Lam VL, Li F, Li J, Li YL, Li Y, Liu X, Lo M, Lopez KE, Melo AA, Moss FR, Nguyen P, Paulino J, Pawar KI, Peters JK, Pospiech TH, Safari M, Sangwan S, Schaefer K, Thomas PV, Thwin AC, Trenker R, Tse E, Tsui TKM, Wang F, Whitis N, Yu Z, Zhang K, Zhang Y, Zhou F, Saltzberg D, QCRG Structural Biology Consortium, Hodder AJ, Shun-Shion AS, Williams DM, White KM, Rosales R, Kehrer T, Miorin L, Moreno E, Patel AH, Rihn S, Khalid MM, Vallejo-Gracia A, Fozouni P, Simoneau CR, Roth TL, Wu D, Karim MA, Ghoussaini M, Dunham I, Berardi F, Weigang S, Chazal M, Park J, Logue J, McGrath M, Weston S, Haupt R, Hastie CJ, Elliott M, Brown F, Burness KA, Reid E, Dorward M, Johnson C, Wilkinson SG, Geyer A, Giesel DM, Baillie C, Raggett S, Leech H, Toth R, Goodman N, Keough KC, Lind AL, Zoonomia Consortium, Klesh RJ, Hemphill KR, Carlson-Stevermer J, Oki J, Holden K, Maures T, Pollard KS, Sali A, Agard DA, Cheng Y, Fraser JS, Frost A, Jura N, Kortemme T, Manglik A, Southworth DR, Stroud RM, Alessi DR, Davies P, Frieman MB, Ideker T, Abate C, Jouvenet N, Kochs G, Shoichet B, Ott M, Palmarini M, Shokat KM, García-Sastre A, Rassen JA, Grosse R, Rosenberg OS, Verba KA, Basler CF, Vignuzzi M, Peden AA, Beltrao P, Krogan NJ. Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Science. 2020 12 04; 370(6521).  View on PubMed
  11. Li F, Eriksen J, Finer-Moore J, Chang R, Nguyen P, Bowen A, Myasnikov A, Yu Z, Bulkley D, Cheng Y, Edwards RH, Stroud RM. Ion transport and regulation in a synaptic vesicle glutamate transporter. Science. 2020 05 22; 368(6493):893-897.  View on PubMed
  12. Kumar H, Finer-Moore J, Smirnova I, Kasho V, Pardon E, Steyaert J, Kaback HR, Stroud RM. Diversity in kinetics correlated with structure in nano body-stabilized LacY. PLoS One. 2020; 15(5):e0232846.  View on PubMed
  13. Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, White KM, O'Meara MJ, Rezelj VV, Guo JZ, Swaney DL, Tummino TA, Hüttenhain R, Kaake RM, Richards AL, Tutuncuoglu B, Foussard H, Batra J, Haas K, Modak M, Kim M, Haas P, Polacco BJ, Braberg H, Fabius JM, Eckhardt M, Soucheray M, Bennett MJ, Cakir M, McGregor MJ, Li Q, Meyer B, Roesch F, Vallet T, Mac Kain A, Miorin L, Moreno E, Naing ZZC, Zhou Y, Peng S, Shi Y, Zhang Z, Shen W, Kirby IT, Melnyk JE, Chorba JS, Lou K, Dai SA, Barrio-Hernandez I, Memon D, Hernandez-Armenta C, Lyu J, Mathy CJP, Perica T, Pilla KB, Ganesan SJ, Saltzberg DJ, Rakesh R, Liu X, Rosenthal SB, Calviello L, Venkataramanan S, Liboy-Lugo J, Lin Y, Huang XP, Liu Y, Wankowicz SA, Bohn M, Safari M, Ugur FS, Koh C, Savar NS, Tran QD, Shengjuler D, Fletcher SJ, O'Neal MC, Cai Y, Chang JCJ, Broadhurst DJ, Klippsten S, Sharp PP, Wenzell NA, Kuzuoglu-Ozturk D, Wang HY, Trenker R, Young JM, Cavero DA, Hiatt J, Roth TL, Rathore U, Subramanian A, Noack J, Hubert M, Stroud RM, Frankel AD, Rosenberg OS, Verba KA, Agard DA, Ott M, Emerman M, Jura N, von Zastrow M, Verdin E, Ashworth A, Schwartz O, d'Enfert C, Mukherjee S, Jacobson M, Malik HS, Fujimori DG, Ideker T, Craik CS, Floor SN, Fraser JS, Gross JD, Sali A, Roth BL, Ruggero D, Taunton J, Kortemme T, Beltrao P, Vignuzzi M, García-Sastre A, Shokat KM, Shoichet BK, Krogan NJ. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature. 2020 07; 583(7816):459-468.  View on PubMed
  14. Dickinson MS, Myasnikov A, Eriksen J, Poweleit N, Stroud RM. Resting state structure of the hyperdepolarization activated two-pore channel 3. Proc Natl Acad Sci U S A. 2020 01 28; 117(4):1988-1993.  View on PubMed
  15. Vecchio AJ, Stroud RM. Claudin-9 structures reveal mechanism for toxin-induced gut barrier breakdown. Proc Natl Acad Sci U S A. 2019 09 03; 116(36):17817-17824.  View on PubMed
  16. Torres SE, Gallagher CM, Plate L, Gupta M, Liem CR, Guo X, Tian R, Stroud RM, Kampmann M, Weissman JS, Walter P. Ceapins block the unfolded protein response sensor ATF6α by inducing a neomorphic inter-organelle tether. Elife. 2019 05 31; 8.  View on PubMed
  17. Leano JB, Batarni S, Eriksen J, Juge N, Pak JE, Kimura-Someya T, Robles-Colmenares Y, Moriyama Y, Stroud RM, Edwards RH. Structures suggest a mechanism for energy coupling by a family of organic anion transporters. PLoS Biol. 2019 05; 17(5):e3000260.  View on PubMed
  18. Crane MJ, Petrone A, Beck RA, Lim MB, Zhou X, Li X, Stroud RM, Pauzauskie PJ. High-pressure, high-temperature molecular doping of nanodiamond. Sci Adv. 2019 May; 5(5):eaau6073.  View on PubMed
  19. Vecchio AJ, Stroud RM. High-Throughput Nano-Scale Characterization of Membrane Proteins Using Fluorescence-Detection Size-Exclusion Chromatography. Methods Mol Biol. 2019; 2025:361-388.  View on PubMed
  20. Kintzer AF, Green EM, Dominik PK, Bridges M, Armache JP, Deneka D, Kim SS, Hubbell W, Kossiakoff AA, Cheng Y, Stroud RM. Structural basis for activation of voltage sensor domains in an ion channel TPC1. Proc Natl Acad Sci U S A. 2018 09 25; 115(39):E9095-E9104.  View on PubMed

Go to UCSF Profiles, powered by CTSI