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. Braxton JR, Shao H, Tse E, Gestwicki JE, Southworth DR. Asymmetric apical domain states of mitochondrial Hsp60 coordinate substrate engagement and chaperonin assembly. bioRxiv. 2023 May 15.  View on PubMed
  2. Echtenkamp FJ, Ishida R, Rivera-Marquez GM, Maisiak M, Johnson OT, Shrimp JH, Sinha A, Ralph SJ, Nisbet I, Cherukuri MK, Gestwicki JE, Neckers LM. Mitoribosome sensitivity to HSP70 inhibition uncovers metabolic liabilities of castration-resistant prostate cancer. PNAS Nexus. 2023 Apr; 2(4):pgad115.  View on PubMed
  3. Proteostasis Consortium, Overall coordination, Elsasser S, Elia LP, Morimoto RI, Powers ET, Harvard Medical School group, Elsasser S, Finley D, University of California, San Francisco and Gladstone Institutes group I, Costa B, Budron M, Tokuno Z, Wang S, Iyer RG, Barth B, Mockler E, Elia LP, Finkbeiner S, University of California, San Francisco group II, Gestwicki JE, Northwestern University group, Richardson RAK, Stoeger T, Morimoto RI, Scripps Research Institute group, Tan EP, Xiao Q, Cole CM, Massey LEA, Garza D, Powers ET, Kelly JW, Stanford University group, Rainbolt TK, Chou CC, Masto VB, Frydman J, New York University group, Nixon RA. A Comprehensive Enumeration of the Human Proteostasis Network. 2. Components of the Autophagy-Lysosome Pathway. bioRxiv. 2023 Mar 24.  View on PubMed
  4. Nadel CM, Thwin AC, Callahan M, Lee K, Connelly E, Craik CS, Southworth DR, Gestwicki JE. The E3 Ubiquitin Ligase, CHIP/STUB1, Inhibits Aggregation of Phosphorylated Proteoforms of Microtubule-associated Protein Tau (MAPT). J Mol Biol. 2023 Mar 09; 168026.  View on PubMed
  5. Xu P, Yang JC, Ning S, Chen B, Nip C, Wei Q, Liu L, Johnson OT, Gao AC, Gestwicki JE, Evans CP, Liu C. Allosteric inhibition of HSP70 in collaboration with STUB1 augments enzalutamide efficacy in antiandrogen resistant prostate tumor and patient-derived models. Pharmacol Res. 2023 03; 189:106692.  View on PubMed
  6. Montgomery KM, Carroll EC, Thwin AC, Quddus AY, Hodges P, Southworth DR, Gestwicki JE. Chemical Features of Polyanions Modulate Tau Aggregation and Conformational States. J Am Chem Soc. 2023 Feb 08.  View on PubMed
  7. Wu T, Yu JC, Suresh A, Gale-Day ZJ, Alteen MG, Woo AS, Millbern Z, Johnson OT, Carroll EC, Partch CL, Fourches D, Vinueza NR, Vocadlo DJ, Gestwicki JE. Conformationally responsive dyes enable protein-adaptive differential scanning fluorimetry. bioRxiv. 2023 Jan 28.  View on PubMed
  8. Gahbauer S, Correy GJ, Schuller M, Ferla MP, Doruk YU, Rachman M, Wu T, Diolaiti M, Wang S, Neitz RJ, Fearon D, Radchenko DS, Moroz YS, Irwin JJ, Renslo AR, Taylor JC, Gestwicki JE, von Delft F, Ashworth A, Ahel I, Shoichet BK, Fraser JS. Iterative computational design and crystallographic screening identifies potent inhibitors targeting the Nsp3 macrodomain of SARS-CoV-2. Proc Natl Acad Sci U S A. 2023 01 10; 120(2):e2212931120.  View on PubMed
  9. Kuzuoglu-Ozturk D, Aksoy O, Schmidt C, Lea R, Larson JD, Phelps RRL, Nasholm N, Holt M, Contreras A, Huang M, Wong-Michalak S, Shao H, Wechsler-Reya R, Phillips JJ, Gestwicki JE, Ruggero D, Weiss WA. N-myc-Mediated Translation Control Is a Therapeutic Vulnerability in Medulloblastoma. Cancer Res. 2023 01 04; 83(1):130-140.  View on PubMed
  10. 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. Iterative computational design and crystallographic screening identifies potent inhibitors targeting the Nsp3 Macrodomain of SARS-CoV-2. bioRxiv. 2022 Jul 28.  View on PubMed
  11. 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 08 18; 29(8):1288-1302.e7.  View on PubMed
  12. 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
  13. 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
  14. 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
  15. Gestwicki JE. Multi-protein complexes as drug targets. Cell Chem Biol. 2022 05 19; 29(5):713-715.  View on PubMed
  16. 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
  17. 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
  18. 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
  19. 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
  20. 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

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