Research Summary

The Gestwicki Laboratory is interested in molecular chaperones, protein homeostasis and protein misfolding disorders. To approach the big questions in this area, we use a chemical biology strategy that includes the discovery and optimization of new chemical inhibitors. We use these chemical probes to acutely perturb chaperone functions, revealing how these systems normally protect from cancer and neurodegeneration. Many of our chemical probes target allosteric and protein-protein interaction sites on the molecular chaperones and we have a significant interest in discovering inhibitors of "difficult" targets. We hope to better understand the logic of protein folding and misfolding and use this information to design more effective therapies.

Research Funding

  • September 30, 2021 - July 31, 2026 - Analysis of chemical modulators for corneal endothelial dystrophies , Co-Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01EY032161
  • August 5, 2021 - May 31, 2025 - Differential Scanning Fluorimetry (DSF) Methods for Studying Protein Stability , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01GM141299
  • September 1, 2020 - August 31, 2024 - Probing the Role of Chaperone-TPR Complexes in Tau Proteostasis , Principal Investigator . Sponsor: NIH, Sponsor Award ID: RF1AG068125
  • June 1, 2014 - February 28, 2019 - Exploration of Molecular Chaperone Complexes During Active Protein Triage , Co-Investigator . Sponsor: NIH, Sponsor Award ID: R01GM109896

Education

State University of New York - Fredonia, B.S., 1997, Chemistry
University of Wisconsin – Madison (with Laura L. Kiessling), PhD, 2002, Biochemistry
Stanford University (with Gerald R. Crabtree), 2005, Post-doctoral, Chemical Biology

Honors & Awards

  • 2020
    Everson Lecture, University of Wisconsin-Madison
  • 2019
    Chair, Bioorganic Chemistry GRC
  • 2018
    Elected Fellow, Cell Stress Society International (CSSI)
  • 2018
    Keynote Speaker, 9th International Symposium on Heat Shock Proteins in Biology and Medicine
  • 2018, 2019
    Dean's Apple Award, Outstanding Teaching in UCSF School of Pharmacy
  • 2017
    Director, Chemistry & Chemical Biology Ph.D. Program UCSF
  • 2015
    UCSF School of Pharmacy, Excellence in Teaching
  • 2014
    Named "Young Innovator" at UCSF
  • 2012
    Elected Fellow, American Association for the Advancement of Science (AAAS)
  • 2009
    National Science Foundation CAREER award

Selected Publications

  1. Ferguson ID, Lin YT, Lam C, Shao H, Tharp KM, Hale M, Kasap C, Mariano MC, Kishishita A, Patiño Escobar B, Mandal K, Steri V, Wang D, Phojanakong P, Tuomivaara ST, Hann B, Driessen C, Van Ness B, Gestwicki JE, Wiita AP. Allosteric HSP70 inhibitors perturb mitochondrial proteostasis and overcome proteasome inhibitor resistance in multiple myeloma. Cell Chem Biol. 2022 Aug 18; 29(8):1288-1302.e7.  View on PubMed
  2. Shao H, Taguwa S, Gilbert L, Shkedi A, Sannino S, Guerriero CJ, Gale-Day ZJ, Young ZT, Brodsky JL, Weissman J, Gestwicki JE, Frydman J. A campaign targeting a conserved Hsp70 binding site uncovers how subcellular localization is linked to distinct biological activities. Cell Chem Biol. 2022 08 18; 29(8):1303-1316.e3.  View on PubMed
  3. Gahbauer S, Correy GJ, Schuller M, Ferla MP, Doruk YU, Rachman M, Wu T, Diolaiti M, Wang S, Neitz RJ, Fearon D, Radchenko D, Moroz Y, Irwin JJ, Renslo AR, Taylor JC, Gestwicki JE, von Delft F, Ashworth A, Ahel I, Shoichet BK, Fraser JS. Structure-based inhibitor optimization for the Nsp3 Macrodomain of SARS-CoV-2. bioRxiv. 2022 Jun 28.  View on PubMed
  4. Johnson OT, Gestwicki JE. Multivalent protein-protein interactions are pivotal regulators of eukaryotic Hsp70 complexes. Cell Stress Chaperones. 2022 07; 27(4):397-415.  View on PubMed
  5. Carrettiero DC, Almeida MC, Longhini AP, Rauch JN, Han D, Zhang X, Najafi S, Gestwicki JE, Kosik KS. Stress routes clients to the proteasome via a BAG2 ubiquitin-independent degradation condensate. Nat Commun. 2022 06 02; 13(1):3074.  View on PubMed
  6. Gestwicki JE. Multi-protein complexes as drug targets. Cell Chem Biol. 2022 05 19; 29(5):713-715.  View on PubMed
  7. Wang C, Fan L, Khawaja RR, Liu B, Zhan L, Kodama L, Chin M, Li Y, Le D, Zhou Y, Condello C, Grinberg LT, Seeley WW, Miller BL, Mok SA, Gestwicki JE, Cuervo AM, Luo W, Gan L. Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy. Nat Commun. 2022 04 12; 13(1):1969.  View on PubMed
  8. Opoku-Nsiah KA, de la Pena AH, Williams SK, Chopra N, Sali A, Lander GC, Gestwicki JE. The YΦ motif defines the structure-activity relationships of human 20S proteasome activators. Nat Commun. 2022 03 09; 13(1):1226.  View on PubMed
  9. Johnson OT, Nadel CM, Carroll EC, Arhar T, Gestwicki JE. Two distinct classes of cochaperones compete for the EEVD motif in heat shock protein 70 to tune its chaperone activities. J Biol Chem. 2022 03; 298(3):101697.  View on PubMed
  10. Shkedi A, Taylor IR, Echtenkamp F, Ramkumar P, Alshalalfa M, Rivera-Márquez GM, Moses MA, Shao H, Karnes RJ, Neckers L, Feng F, Kampmann M, Gestwicki JE. Selective vulnerabilities in the proteostasis network of castration-resistant prostate cancer. Cell Chem Biol. 2022 03 17; 29(3):490-501.e4.  View on PubMed
  11. Hong SK, Starenki D, Johnson OT, Gestwicki JE, Park JI. Analogs of the Heat Shock Protein 70 Inhibitor MKT-077 Suppress Medullary Thyroid Carcinoma Cells. Int J Mol Sci. 2022 Jan 19; 23(3).  View on PubMed
  12. Arhar T, Shkedi A, Nadel CM, Gestwicki JE. The interactions of molecular chaperones with client proteins: why are they so weak? J Biol Chem. 2021 11; 297(5):101282.  View on PubMed
  13. Shkedi A, Adkisson M, Schroeder A, Eckalbar WL, Kuo SY, Neckers L, Gestwicki JE. Inhibitor Combinations Reveal Wiring of the Proteostasis Network in Prostate Cancer Cells. J Med Chem. 2021 10 14; 64(19):14809-14821.  View on PubMed
  14. Lee K, Thwin AC, Nadel CM, Tse E, Gates SN, Gestwicki JE, Southworth DR. The structure of an Hsp90-immunophilin complex reveals cochaperone recognition of the client maturation state. Mol Cell. 2021 09 02; 81(17):3496-3508.e5.  View on PubMed
  15. Tharp KM, Higuchi-Sanabria R, Timblin GA, Ford B, Garzon-Coral C, Schneider C, Muncie JM, Stashko C, Daniele JR, Moore AS, Frankino PA, Homentcovschi S, Manoli SS, Shao H, Richards AL, Chen KH, Hoeve JT, Ku GM, Hellerstein M, Nomura DK, Saijo K, Gestwicki J, Dunn AR, Krogan NJ, Swaney DL, Dillin A, Weaver VM. Adhesion-mediated mechanosignaling forces mitohormesis. Cell Metab. 2021 07 06; 33(7):1322-1341.e13.  View on PubMed
  16. Evans CG, Gestwicki JE. Retraction of "Enantioselective Organocatalytic Hantzsch Synthesis of Polyhydroquinolines". Org Lett. 2021 May 07; 23(9):3802.  View on PubMed
  17. Caballero B, Bourdenx M, Luengo E, Diaz A, Sohn PD, Chen X, Wang C, Juste YR, Wegmann S, Patel B, Young ZT, Kuo SY, Rodriguez-Navarro JA, Shao H, Lopez MG, Karch CM, Goate AM, Gestwicki JE, Hyman BT, Gan L, Cuervo AM. Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice. Nat Commun. 2021 04 14; 12(1):2238.  View on PubMed
  18. Schuller M, Correy GJ, Gahbauer S, Fearon D, Wu T, Díaz RE, Young ID, Carvalho Martins L, Smith DH, Schulze-Gahmen U, Owens TW, Deshpande I, Merz GE, Thwin AC, Biel JT, Peters JK, Moritz M, Herrera N, Kratochvil HT, QCRG Structural Biology Consortium, Aimon A, Bennett JM, Brandao Neto J, Cohen AE, Dias A, Douangamath A, Dunnett L, Fedorov O, Ferla MP, Fuchs MR, Gorrie-Stone TJ, Holton JM, Johnson MG, Krojer T, Meigs G, Powell AJ, Rack JGM, Rangel VL, Russi S, Skyner RE, Smith CA, Soares AS, Wierman JL, Zhu K, O'Brien P, Jura N, Ashworth A, Irwin JJ, Thompson MC, Gestwicki JE, von Delft F, Shoichet BK, Fraser JS, Ahel I. Fragment binding to the Nsp3 macrodomain of SARS-CoV-2 identified through crystallographic screening and computational docking. Sci Adv. 2021 04; 7(16).  View on PubMed
  19. Shao H, Li X, Hayashi S, Bertron JL, Schwarz DMC, Tang BC, Gestwicki JE. Inhibitors of heat shock protein 70 (Hsp70) with enhanced metabolic stability reduce tau levels. Bioorg Med Chem Lett. 2021 06 01; 41:128025.  View on PubMed
  20. Tao J, Berthet A, Citron YR, Tsiolaki PL, Stanley R, Gestwicki JE, Agard DA, McConlogue L. Hsp70 chaperone blocks α-synuclein oligomer formation via a novel engagement mechanism. J Biol Chem. 2021 Jan-Jun; 296:100613.  View on PubMed

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