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

  • August 15, 2016 - May 31, 2018 - Activation of the 20S Proteasome to Normalize Tau Homeostasis, Principal Investigator. Sponsor: NIH, Sponsor Award ID: R21AG053619
  • June 1, 2014 - February 28, 2018 - Exploration of Molecular Chaperone Complexes During Active Protein Triage, Co-Investigator. Sponsor: NIH/NIGMS, Sponsor Award ID: R01GM109896
  • February 1, 2012 - January 31, 2014 - Natural Product-Inspired Method for Enhancing HIV Protease Inhibitors, Principal Investigator. Sponsor: NIH, Sponsor Award ID: R21AI098431
  • August 1, 2012 - March 31, 2013 - Chemical Probes and Chaperone-Accelerated Turnover of Tau, Principal Investigator. Sponsor: NIH, Sponsor Award ID: R21AG042813

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. 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 Oct 05; 101282.  View on PubMed
  2. 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 Oct 14; 64(19):14809-14821.  View on PubMed
  3. 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
  4. 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 Jul 06; 33(7):1322-1341.e13.  View on PubMed
  5. Evans CG, Gestwicki JE. Retraction of "Enantioselective Organocatalytic Hantzsch Synthesis of Polyhydroquinolines". Org Lett. 2021 May 07; 23(9):3802.  View on PubMed
  6. 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
  7. 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
  8. 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
  9. 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
  10. Abrams J, Arhar T, Mok SA, Taylor IR, Kampmann M, Gestwicki JE. Functional genomics screen identifies proteostasis targets that modulate prion protein (PrP) stability. Cell Stress Chaperones. 2021 03; 26(2):443-452.  View on PubMed
  11. Makley LN, Johnson OT, Ghanakota P, Rauch JN, Osborn D, Wu TS, Cierpicki T, Carlson HA, Gestwicki JE. Chemical validation of a druggable site on Hsp27/HSPB1 using in silico solvent mapping and biophysical methods. Bioorg Med Chem. 2021 03 15; 34:115990.  View on PubMed
  12. Dutta T, Singh H, Gestwicki JE, Blatch GL. Exported plasmodial J domain protein, PFE0055c, and PfHsp70-x form a specific co-chaperone-chaperone partnership. Cell Stress Chaperones. 2021 03; 26(2):355-366.  View on PubMed
  13. Schuller M, Correy GJ, Gahbauer S, Fearon D, Wu T, Díaz RE, Young ID, Martins LC, 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, Neto JB, Cohen AE, Dias A, Douangamath A, Dunnett L, Fedorov O, Ferla MP, Fuchs M, Gorrie-Stone TJ, Holton JM, Johnson MG, Krojer T, Meigs G, Powell AJ, Johannes Gregor Matthias Rack, Rangel VL, Russi S, Skyner RE, Smith CA, Soares AS, Wierman JL, Zhu K, Jura N, Ashworth A, Irwin J, 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. bioRxiv. 2020 Nov 24.  View on PubMed
  14. Nadel CM, Ran X, Gestwicki JE. Luminescence complementation assay for measurement of binding to protein C-termini in live cells. Anal Biochem. 2020 12 15; 611:113947.  View on PubMed
  15. Schwarz DMC, Williams SK, Dillenburg M, Wagner CR, Gestwicki JE. A Phosphoramidate Strategy Enables Membrane Permeability of a Non-nucleotide Inhibitor of the Prolyl Isomerase Pin1. ACS Med Chem Lett. 2020 Sep 10; 11(9):1704-1710.  View on PubMed
  16. Bengoechea R, Findlay AR, Bhadra AK, Shao H, Stein KC, Pittman SK, Daw JA, Gestwicki JE, True HL, Weihl CC. Inhibition of DNAJ-HSP70 interaction improves strength in muscular dystrophy. J Clin Invest. 2020 08 03; 130(8):4470-4485.  View on PubMed
  17. Shao H, Oltion K, Wu T, Gestwicki JE. Differential scanning fluorimetry (DSF) screen to identify inhibitors of Hsp60 protein-protein interactions. Org Biomol Chem. 2020 06 10; 18(22):4157-4163.  View on PubMed
  18. Huang Y, Zhao N, Wang YH, Truillet C, Wei J, Blecha JE, VanBrocklin HF, Seo Y, Sayeed M, Feldman BJ, Aggarwal R, Behr SC, Shao H, Wilson DM, Villanueva-Meyer JE, Gestwicki JE, Evans MJ. A Novel Radioligand Reveals Tissue Specific Pharmacological Modulation of Glucocorticoid Receptor Expression with Positron Emission Tomography. ACS Chem Biol. 2020 06 19; 15(6):1381-1391.  View on PubMed
  19. Wu PK, Hong SK, Starenki D, Oshima K, Shao H, Gestwicki JE, Tsai S, Park JI. Mortalin/HSPA9 targeting selectively induces KRAS tumor cell death by perturbing mitochondrial membrane permeability. Oncogene. 2020 05; 39(21):4257-4270.  View on PubMed
  20. Jackson JW, Rivera-Marquez GM, Beebe K, Tran AD, Trepel JB, Gestwicki JE, Blagg BSJ, Ohkubo S, Neckers LM. Pharmacologic dissection of the overlapping impact of heat shock protein family members on platelet function. J Thromb Haemost. 2020 05; 18(5):1197-1209.  View on PubMed

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