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

  • July 1, 2022 - June 30, 2027 - Research Training in Chemistry and Chemical Biology , Principal Investigator . Sponsor: NIH, Sponsor Award ID: T32GM145460
  • September 30, 2021 - July 31, 2026 - Analysis of chemical modulators for corneal endothelial dystrophies , Co-Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01EY032161
  • September 1, 2023 - August 31, 2025 - Chemical Biology Approaches to Studying Collagen IV Stability , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R21EY035366
  • September 1, 2020 - August 31, 2025 - Probing the Role of Chaperone-TPR Complexes in Tau Proteostasis , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01AG068125
  • July 1, 2023 - June 30, 2025 - Adhesin Amyloid Biology , Co-Principal Investigator . Sponsor: NIH, Sponsor Award ID: R21AI178229
  • 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
  • August 15, 2016 - May 31, 2018 - Activation of the 20S Proteasome to Normalize Tau Homeostasis , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R21AG053619
  • 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
  • February 1, 2008 - March 31, 2013 - Molecular Chaperones and Small Molecules , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01NS059690

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. Carroll EC, Yang H, Powell WC, Charvat AF, Oehler A, Jones JG, Montgomery KM, Yung A, Millbern Z, Taylor AIP, Wilkinson M, Ranson NA, Radford SE, Vinueza NR, DeGrado WF, Mordes DA, Condello C, Gestwicki JE. Author Correction: High-throughput discovery of fluoroprobes that recognize amyloid fibril polymorphs. Nat Chem. 2026 Aug; 18(8):1526. View on PubMed
  2. Moss T, Wooldredge A, Bhakta K, Cronin M, Gestwicki JE, Mukherjee S. Hsp70 is phosphorylated in a conserved response to DNA damage and contributes to cell cycle control. Elife. 2026 May 27; 15. View on PubMed
  3. Chen Y, Bhattacharya S, Bergmann L, Correy GJ, Tan SK, Hou K, Biel JT, Lu L, Bakanas I, Gestwicki JE, Volkov AN, Korendovych IV, Polizzi NF, Fraser JS, DeGrado WF. Emergence of specific binding and catalysis from a designed generalist binding protein. Nat Chem. 2026 Jul; 18(7):1334-1344. View on PubMed
  4. Elsasser S, Powers ET, Stoeger T, Sui X, Kurtzbard RD, Martínez-Botía P, Wangeline MA, Gama AR, Huttlin EL, Elia LP, Kelly JW, Gestwicki JE, Frydman J, Finkbeiner S, Clerico EM, Morimoto RI, Prado MA, Vertegaal ACO, Hofmann K, Finley D. Survey of the human proteostasis network: the ubiquitin-proteasome system. bioRxiv. 2026 Apr 30. View on PubMed
  5. Gu X, Fajtova P, Yan NL, Saxena A, Fei F, Zhu J, Tse E, Melo A, Yoo E, Buchwald NH, Southworth DR, Bogyo M, Derisi JL, Gestwicki JE, O'Donoghue AJ, Sello JK. An Optimized Route to the Syringolin Natural Products Enables Combinatorial Synthesis of Selective, Bioactive Inhibitors of the Plasmodium falciparum 20S Proteasome. J Med Chem. 2026 Apr 23; 69(8):8897-8914. View on PubMed
  6. Shkedi A, Grabinska-Rogala A, Hernandez J, Dutkiewicz R, Marszalek J, Gestwicki JE. High-Throughput Platform for Discovery of Chemical Inhibitors of Heat Shock Protein 70 (Hsp70): Adaptation for the Specialized Bacterial HscA-HscB-IscU Complex. Chem Biol Drug Des. 2026 Mar; 107(3):e70281. View on PubMed
  7. Samelson AJ, Ariqat N, McKetney J, Rohanitazangi G, Parra Bravo C, Bose RS, Travaglini KJ, Lam VL, Goodness D, Ta T, Dixon G, Marzette E, Jin J, Tian R, Tse E, Abskharon R, Pan HS, Carroll EC, Lawrence RE, Gestwicki JE, Rexach JE, Eisenberg DS, Kanaan NM, Southworth DR, Gross JD, Gan L, Swaney DL, Kampmann M. CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis. Cell. 2026 Mar 05; 189(5):1517-1534.e19. View on PubMed
  8. Ahmad T, Alhammadi BA, Almaazmi SY, Arafa S, Blatch GL, Dutta T, Gestwicki JE, Keyzers RA, Meskiri A, Sharafeldin A, Shonhai A, Singh H. Malaria Public Health Status: Global Context and Update on Gulf Cooperation Council Countries. Adv Exp Med Biol. 2026; 1507:35-53. View on PubMed
  9. Kirstein J, Rosenzweig R, De Los Rios P, Genevaux P, Adang C, Andreasson C, Balchin D, Barducci A, Blatch GL, Braun JEA, Brodsky JL, Bukau B, Chapple JP, Cheetham ME, Craig EA, Cyr DM, Dementin S, Faust O, Genest O, Gestwicki JE, Goloubinoff P, Grabinska-Rogala A, Hammond CM, Inoue M, Jiang Y, Joachimiak LA, Kasai A, Klosowska A, Lee HO, Liberek K, Musskopf MK, Linse S, Mayer MP, Mogk A, Mokranjac D, Münch C, Rebeaud ME, Rospert S, Sanagavarapu K, Sahi C, Shalgi R, Sutandy FXR, Tomiczek B, Ushioda R, Weihl CC, Ying Z, Marszalek J, Kampinga HH. J-domain proteins: from molecular mechanisms to diseases. Cell Stress Chaperones. 2025 Dec 19; 31(1):100142. View on PubMed
  10. Moss T, Wooldredge A, Bhakta K, Cronin M, Gestwicki JE, Mukherjee S. A conserved Hsp70 phosphorylation regulates cell cycle progression after DNA damage. bioRxiv. 2025 Sep 06. View on PubMed
  11. Torielli L, Castelli M, Milani F, Heritz JA, Cayaban SJ, Hernandez J, Serapian SA, Magni A, Frasnetti E, Doria F, Pirota V, Wengert LA, Woodford MR, Lodigiani G, Bergamaschi G, Veronesi M, Bandiera T, Girotto S, Paladino A, Prodromou C, Backe SJ, Bourboulia D, Canciani A, Arrigoni C, Lolicato M, Gestwicki JE, Mollapour M, Colombo G. Design of multi-target peptide modulators for protein chaperone networks. Structure. 2025 Nov 06; 33(11):1944-1957.e6. View on PubMed
  12. Carroll EC, Yang H, Powell WC, Charvat AF, Oehler A, Jones JG, Montgomery KM, Yung A, Millbern Z, Taylor AIP, Wilkinson M, Ranson NA, Radford SE, Vinueza NR, DeGrado WF, Mordes DA, Condello C, Gestwicki JE. High-throughput discovery of fluoroprobes that recognize amyloid fibril polymorphs. Nat Chem. 2025 10; 17(10):1565-1575. View on PubMed
  13. Charvat AF, Mason-Chalmers K, Grabinska-Rogala A, Shivakumar S, Gale-Day Z, Wu T, Millbern Z, Grimm JB, Carroll EC, Nilsson KPR, Lavis LD, Vinueza NR, Gestwicki JE. Aurora 2.0: A fluorogenic dye library for expanding the capability of protein-adaptive differential scanning fluorimetry (paDSF). SLAS Discov. 2025 09; 35:100259. View on PubMed
  14. Sang R, Gestwicki JE. Radical Strategy to the Boron-to-Copper Transmetalation Problem: N-Alkylation with Alkylboronic Esters. J Am Chem Soc. 2025 Jul 02; 147(26):23259-23269. View on PubMed
  15. 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. 2025 05 15; 135(10). View on PubMed
  16. Unnikrishnan A, Chung DH, Connelly EJ, Chuo SW, Devi S, Thwin AC, Nadel CM, Tse E, Gestwicki JE, Craik CS, Southworth DR. Structures of Fab-stabilized CHIP reveal a conformational switch important in E3 ligase and chaperone functions. bioRxiv. 2025 May 15. View on PubMed
  17. Torielli L, Guarra F, Shao H, Gestwicki JE, Serapian SA, Colombo G. Pathogenic mutation impairs functional dynamics of Hsp60 in mono- and oligomeric states. Nat Commun. 2025 Apr 03; 16(1):3158. View on PubMed
  18. Zhang JZ, Greenwood N, Hernandez J, Cuperus JT, Huang B, Ryder BD, Queitsch C, Gestwicki JE, Baker D. De novo designed Hsp70 activator dissolves intracellular condensates. Cell Chem Biol. 2025 Mar 20; 32(3):463-473.e6. View on PubMed
  19. Chung DH, Connelly EJ, Unnikrishnan A, Chuo SW, Wucherer K, Nadel CM, Gestwicki JE, Southworth DR, Craik CS. Recombinant antibodies inhibit enzymatic activity of the E3 ubiquitin ligase CHIP via multiple mechanisms. J Biol Chem. 2025 03; 301(3):108220. View on PubMed
  20. Pokhrel S, Devi S, Gestwicki JE. Chaperone-dependent and chaperone-independent functions of carboxylate clamp tetratricopeptide repeat (CC-TPR) proteins. Trends Biochem Sci. 2025 Feb; 50(2):121-133. View on PubMed

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