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
  • April 1, 1979 - December 31, 2016 - Molecular Basis for Transmembrane Conduction & Signaling , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R37GM024485
  • September 30, 2010 - June 30, 2016 - Center for Structure of Membrane Proteins , Principal Investigator . Sponsor: NIH, Sponsor Award ID: U54GM094625
  • September 24, 2004 - August 31, 2015 - Membrane Protein Expression Center , Principal Investigator . Sponsor: NIH, Sponsor Award ID: P50GM073210
  • March 1, 1982 - May 31, 2015 - Bio-Organic Biomedical Mass Spectrometry Resource , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P41RR001614
  • March 1, 1980 - February 28, 2015 - A Synchroton Radiation Structural Biology Resource , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P41RR001209
  • March 1, 1985 - December 31, 2014 - 3 D Electron Microscopy of Macromolecules , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P41RR002250
  • September 28, 2012 - August 31, 2013 - 4th NIH Roadmap Meeting on Membrane Protein Structures and Complexes , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R13GM105348
  • May 1, 1996 - May 31, 2013 - RNA Modification Enzymes: Methyltransferase/PSI-synthase , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01GM051232
  • June 1, 1976 - September 14, 2012 - Resource for Biocomputing, Visualization, and Informatics , Co-Investigator . Sponsor: NIH/NCRR, Sponsor Award ID: P41RR001081
  • February 20, 2010 - February 19, 2012 - Anachem Lipidic Cubic Phase Crystallization Robot , Principal Investigator . Sponsor: NIH, Sponsor Award ID: S10RR027234
  • July 4, 2005 - June 30, 2011 - Specialized Center for the Protein Structure Initiative , Principal Investigator . Sponsor: NIH, Sponsor Award ID: U54GM074929
  • January 1, 2000 - June 30, 2009 - Signal Sequence Recognition and Protein Targeting , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01GM060641
  • September 1, 1997 - August 31, 2007 - Structure Biology and Targeted Drug Design for AIDS , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P01GM056531
  • January 1, 1995 - June 30, 2006 - STRUCTURE BASED DRUG DESIGN , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01CA063081
  • April 1, 2005 - March 31, 2006 - 2005 Mechanisms of Membrane Transport Gordon Conference , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R13DK071453
  • September 1, 1978 - February 28, 2002 - THYMIDYLATE SYNTHASE , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01CA014394
  • September 1, 1987 - August 31, 1997 - STRUCTURAL BIOLOGY AND TARGETED DRUG DESIGN FOR AIDS , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P01GM039552
  • August 12, 1991 - September 30, 1993 - AREA SENSITIVE DETECTOR FOR PROTEIN CRYSTALLOGRAPHY , Principal Investigator . Sponsor: NIH, Sponsor Award ID: S10RR006474
  • June 1, 1983 - May 31, 1993 - STRUCTURE AND FUNCTION OF BACTERIORHODOPSIN , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01GM032079
  • June 1, 1980 - June 30, 1991 - LIGHT-ENERGY AND SIGNAL-TRANSDUCING MEMBRANES , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P01GM027057
  • December 20, 1985 - December 19, 1986 - AREA SENSITIVE DECTECTOR FOR PROTEIN CRYSTALLOGRAPHY , Principal Investigator . Sponsor: NIH, Sponsor Award ID: S10RR002705
  • July 1, 1985 - June 30, 1986 - THE CRYSTALLIZATION OF MEMBRANE PROTEINS , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R13AM036248

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. Khandelwal NK, Gupta M, Gomez JE, Barkho S, Guan Z, Eng AY, Kawate T, Balasubramani SG, Sali A, Hung DT, Stroud RM. Structure and inhibition mechanisms of Mycobacterium tuberculosis essential transporter efflux protein A. Nat Commun. 2025 Apr 01; 16(1):3139.  View on PubMed
  2. Gupta M, Khandelwal NK, Nelson A, Hwang P, Pourmal S, Bennett JL, Stroud RM. Structural basis of aquaporin-4 autoantibody binding in neuromyelitis optica. Sci Adv. 2025 Feb 21; 11(8):eadq7560.  View on PubMed
  3. Khandelwal NK, Gupta M, Kumar P, Balasubramani SG, Echeverria I, Stroud RM. Structural basis of disease mutation and substrate recognition by the human SLC2A9 transporter. Proc Natl Acad Sci U S A. 2025 Feb 18; 122(7):e2418282122.  View on PubMed
  4. Khandelwal NK, Gupta M, Gomez JE, Barkho S, Guan Z, Eng AY, Kawate T, Balasubramani SG, Sali A, Hung DT, Stroud RM. Structure and inhibition mechanisms of Mycobacterium tuberculosis essential transporter efflux protein A. bioRxiv. 2024 Sep 05.  View on PubMed
  5. Chen DF, Roe LT, Li Y, Borges AL, Zhang JY, Babbar P, Maji S, Stevens MGV, Correy GJ, Diolaiti ME, Smith DH, Ashworth A, Stroud RM, Kelly MJS, Bondy-Denomy J, Fraser JS. AcrIF11 is a potent CRISPR-specific ADP-ribosyltransferase encoded by phage and plasmid. bioRxiv. 2024 Aug 26.  View on PubMed
  6. Kumar H, Bajaj A, Kumar P, Aggarwal R, Chalia V, Pradhan RK, Yadav R, Sinha S, Agarwal V, Harries W, Dua M, Stroud RM, Johri AK. Biochemical characterization of a high affinity phosphate transporter (PiPT) from root endophyte fungus Piriformospora indica. Protein Expr Purif. 2024 Nov; 223:106559.  View on PubMed
  7. Zhao B, Cao Z, Zheng Y, Nguyen P, Bowen A, Edwards RH, Stroud RM, Zhou Y, Van Lookeren Campagne M, Li F. Structural and mechanistic insights into a lysosomal membrane enzyme HGSNAT involved in Sanfilippo syndrome. Nat Commun. 2024 Jun 25; 15(1):5388.  View on PubMed
  8. Gupta M, Khandelwal NK, Nelson A, Hwang P, Pourmal S, Bennett JL, Stroud RM. Structural Basis of Aquaporin-4 Autoantibody Binding in Neuromyelitis Optica. bioRxiv. 2024 May 14.  View on PubMed
  9. Liu Y, Li C, Gupta M, Stroud RM, Voth GA. Kinetic network modeling with molecular simulation inputs: A proton-coupled phosphate symporter. Biophys J. 2024 Dec 17; 123(24):4191-4199.  View on PubMed
  10. Pourmal S, Green E, Bajaj R, Chemmama IE, Knudsen GM, Gupta M, Sali A, Cheng Y, Craik CS, Kroetz DL, Stroud RM. Structural basis of prostaglandin efflux by MRP4. Nat Struct Mol Biol. 2024 Apr; 31(4):621-632.  View on PubMed
  11. Lu J, Dreyer I, Dickinson MS, Panzer S, Jaslan D, Navarro-Retamal C, Geiger D, Terpitz U, Becker D, Stroud RM, Marten I, Hedrich R. Vicia faba SV channel VfTPC1 is a hyperexcitable variant of plant vacuole Two Pore Channels. Elife. 2023 Nov 22; 12.  View on PubMed
  12. Batarni S, Nayak N, Chang A, Li F, Hareendranath S, Zhou L, Xu H, Stroud R, Eriksen J, Edwards RH. Substrate recognition and proton coupling by a bacterial member of solute carrier family 17. J Biol Chem. 2023 05; 299(5):104646.  View on PubMed
  13. Kim SK, Dickinson MS, Finer-Moore J, Guan Z, Kaake RM, Echeverria I, Chen J, Pulido EH, Sali A, Krogan NJ, Rosenberg OS, Stroud RM. Structure and dynamics of the essential endogenous mycobacterial polyketide synthase Pks13. Nat Struct Mol Biol. 2023 03; 30(3):296-308.  View on PubMed
  14. Kim SK, Dickinson MS, Finer-Moore J, Guan Z, Kaake RM, Echeverria I, Chen J, Pulido EH, Sali A, Krogan NJ, Rosenberg OS, Stroud RM. Structure and dynamics of the essential endogenous mycobacterial polyketide synthase Pks13. bioRxiv. 2023 Jan 28.  View on PubMed
  15. Costantino L, Ferrari S, Santucci M, Salo-Ahen OMH, Carosati E, Franchini S, Lauriola A, Pozzi C, Trande M, Gozzi G, Saxena P, Cannazza G, Losi L, Cardinale D, Venturelli A, Quotadamo A, Linciano P, Tagliazucchi L, Moschella MG, Guerrini R, Pacifico S, Luciani R, Genovese F, Henrich S, Alboni S, Santarem N, da Silva Cordeiro A, Giovannetti E, Peters GJ, Pinton P, Rimessi A, Cruciani G, Stroud RM, Wade RC, Mangani S, Marverti G, D'Arca D, Ponterini G, Costi MP. Destabilizers of the thymidylate synthase homodimer accelerate its proteasomal degradation and inhibit cancer growth. Elife. 2022 12 07; 11.  View on PubMed
  16. Li F, Eriksen J, Finer-Moore J, Stroud RM, Edwards RH. Diversity of function and mechanism in a family of organic anion transporters. Curr Opin Struct Biol. 2022 08; 75:102399.  View on PubMed
  17. 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
  18. Dickinson MS, Pourmal S, Gupta M, Bi M, Stroud RM. Symmetry Reduction in a Hyperpolarization-Activated Homotetrameric Ion Channel. Biochemistry. 2022 10 18; 61(20):2177-2181.  View on PubMed
  19. 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
  20. 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

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