Aashish Manglik, M.D., Ph.D. Curriculum Vitae

Transcription

1 Aashish Manglik, M.D., Ph.D. Curriculum Vitae Beckman Building 279 Campus Drive, Lab B101 Stanford, CA Research Profile Cellular signaling plays a critical role in normal physiology with aberrant signaling responsible for many pathophysiologic states. My research examines the molecular basis of cellular signaling as mediated by the largest family of transmembrane receptors in the human genome, the G protein-coupled receptors (GPCRs). We utilize a broad range of methods in biophysics and biochemistry to understand how these signaling proteins function at the molecular level and leverage these insights towards the development of therapeutics with unique signaling properties and novel in vivo biology. Education B.A., Chemistry and Biology, Washington University in St. Louis Graduated summa cum laude Advisor: Jeffrey McKinney Thesis: Mechanisms mediating Salmonella-cancer cell interactions Ph.D., Biophysics, Stanford University School of Medicine Advisor: Brian K. Kobilka Thesis: Structural dynamics of G protein-coupled receptor activation M.D., Medical Scientist Training Program, Stanford University School of Medicine Academic Appointments 2016 Stanford Distinguished Fellow, Stanford University School of Medicine New fellows program instituted by Stanford University to enable early transition to independence for outstanding graduates of the MD/PhD program Grants, Fellowships, and Awards 2004 National Merit Scholar 2005 Howard Hughes Medical Institute Undergraduate Research Fellowship 2006 Alpha Epsilon Delta: Premedical honorary organization 2007 Barry M. Goldwater Scholarship, Honorable Mention 2008 Spector Award for Best Undergraduate Biology Honors Thesis, Washington University 2011 American Heart Association Predoctoral Fellowship 2013 Scientific American s 30 under National Institutes of Health Early Independence Award Teaching Experience 2006 Washington University in St. Louis, Genetics Teaching Assistant 2007 Washington University in St. Louis, Advanced Biochemistry Teaching Assistant Stanford University School of Medicine, Pharmacology Teaching Assistant 2012 Stanford University School of Medicine, Cardiovascular Physiology Teaching Assistant

2 Aashish Manglik, CV 2 Consulting 2014 Ab Initio Biotherapeutics, Co-founder and Scientific Advisory Board 2016 Epiodyne, Co-founder and Scientific Advisory Board Publications * denotes equal contribution 1. Manglik A*, Lin H*, Aryal D*, McCorvy JD, Dengler D, Corder G, Levit A, Kling RC, Bernat V, Hubner H, Huang XP, Sassano MF, Giguere P, Lober S, Duan D, Scherrer G, Kobilka BK, Gmeiner P, Roth BL, Shoichet BK. Structure based discovery of opioid analgesics with reduced side effects. Nature. 537(7619): (2016) 2. Staus DP*, Strachan RT*, Manglik A*, Pani B, Kahsai AW, Kim TH, Wingler LM, Ahn S, Chatterjee A, Masoudi A, Kruse AC, Pardon E, Steyaert J, Weis WI, Prosser RS, Kobilka BK, Costa T, Lefkowitz RJ. Allosteric nanobodies reveal the dynamic range and diverse mechanisms of GPCR activation. Nature. 535(7612): (2016) 3. DeVree B, Mahoney J, Velez-Ruiz GA, Rasmussen SGF, Kuszak AJ, Edwald E, Fung JJ, Manglik A, Masureel M, Du Y, Matt RA, Pardon E, Steyaert J, Kobilka BK, Sunahara RK. Allosteric coupling from G protein to the agonist binding pocket in GPCRs. Nature. 535(7610):182-6 (2016) 4. Schmidt HR, Zheng S, Gurpinar E, Koehl A, Manglik A, Kruse AC. Crystal structure of the human σ1 receptor. Nature. 532(7600): (2016) 5. Baxter EL, Aguila L, Alonso-Mori R, Barnes CO, Bonagura CA, Brehmer W, Brunger AT, Calero G, Caradoc-Davies TT, Chatterjee R, Degrado WF, Fraser JS, Ibrahim M, Kern J, Kobilka BK, Kruse AC, Larsson KM, Lemke HT, Lyubimov AY, Manglik A, McPhillips SE, Norgren E, Pang SS, Soltis SM, Song J, Thomaston J, Tsai Y, Weis WI, Woldeyes RA, Yachandra V, Yano J, Zouni A, Cohen AE. High-density grids for efficient data collection from multiple crystals. Acta Crystallogr D Struct Biol. 72(Pt 1):2-11 (2016) 6. Maute RL, Gordon SR, Mayer AT, McCracken MN, Natarajan A, Ring NG, Kimura R, Tsai JM, Manglik A, Kruse AC, Gambhir SS, Weissman IL, Ring AM. Engineering high-affinity PD-1 variants for optimized immunotherapy and immuno-pet imaging. PNAS. 112(47):E (2015) 7. Huang W*, Manglik A* #, Venkatakrishnan AJ, Laeremans T, Feinberg EN, Sanborn AL, Kato HE, Livingston KE, Thorsen TS, Kling R, Granier S, Gmeiner P, Husbands SM, Traynor JR, Weis WI, Steyaert J, Dror RO, Kobilka BK #. Structural insights into μ-opioid receptor activation. Nature. 524(7565): (2015) # Corresponding Author 8. Sounier R, Mas C, Steyaert J, Laeremans T, Manglik A, Huang W, Kobilka BK, Demene H, Granier S. Propagation of conformational changes during μ-opioid receptor activation. Nature. 524(7565):375-8 (2015) 9. Dror RO, Mildorf TJ, Hilger D, Manglik A, Borhani DW, Arlow DH, Philippsen A, Villanueva N, Yang Z, Lerch MT, Hubbell WL, Kobilka BK, Sunahara RK, Shaw DE. Structural basis for nucleotide exchange in heterotrimeric G proteins. Science. 348(6241): (2015) 10. / 11. Ye L, Larda ST, Frank Li YF, Manglik A, Prosser RS. A comparison of chemical shift sensitivity of trifluoromethyl tags: optimizing resolution in 19F NMR studies of proteins. Journal of Biomolecular

3 Aashish Manglik, CV 3 NMR. 62(1): (2015) 12. Li L, Homan KT, Vishnivetskiy SA, Manglik A, Tesmer JJ, Gurevich VV, Gurevich EV. G Proteincoupled Receptor Kinases of the GRK4 Protein Subfamily Phosphorylate Inactive G Protein-coupled Receptors (GPCRs). Journal of Biological Chemistry. 290(17): (2015) 13. Cohen AE, Soltis SM, González A, Aguila L, Alonso-Mori R, Barnes CO, Baxter EL, Brehmer W, Brewster AS, Brunger AT, Calero G, Chang JF, Chollet M, Ehrensberger P, Eriksson TL, Feng Y, Hattne J, Hedman B, Hollenbeck M, Holton JM, Keable S, Kobilka BK, Kovaleva EG, Kruse AC, Lemke HT, Lin G, Lyubimov AY, Manglik A, Mathews II, McPhillips SE, Nelson S, Peters JW, Sauter NK, Smith CA, Song J, Stevenson HP, Tsai Y, Uervirojnangkoorn M, Vinetsky V, Wakatsuki S, Weis WI, Zadvornyy OA, Zeldin OB, Zhu D, Hodgson KO. Goniometer-based femtosecond crystallography with X-ray free electron lasers. PNAS. 111(48): (2014) 14. Weichert D, Kruse AC, Manglik A, Hiller C, Zhang C, Hübner H, Kobilka BK, Gmeiner P. Covalent agonists for studying G protein-coupled receptor activation. Proc Natl Acad Sci USA. 29: (2014) 15. Manglik A, Kobilka B. The role of protein dynamics in GPCR function: insights from the β2ar and rhodopsin. Current Opinion in Cell Biology. 27C: (2014) 16. Kruse AC, Ring AM, Manglik A, Hu J, Hu K, Eitel K, Hübner H, Pardon E, Valant C, Sexton PM, Christopoulos A, Felder CC, Gmeiner P, Steyaert J, Weis WI, Garcia KC, Wess J, Kobilka BK. Activation and allosteric modulation of a muscarinic acetylcholine receptor. Nature. 504(7478): (2013). 17. Kruse AC, Manglik A, Kobilka BK, Weis WI. Applications of molecular replacement to G proteincoupled receptors. Acta Crystallographica D. 69(Pt 11): (2013) 18. Ring AM*, Manglik A*, Kruse AC*, Enos MD, Weis WI, Garcia KC, Kobilka BK. Adrenaline-activated structure of β2-adrenoceptor stabilized by an engineered nanobody. Nature. (2013) 19. Kim TH, Chung KY, Manglik A, Hansen AL, Dror RO, Mildorf TJ, Shaw DE, Kobilka BK, Prosser RS. The Role of Ligands on the Equilibria Between Functional States of a G Protein-Coupled Receptor. JACS. 135(25): (2013) 20. Shukla AK*, Manglik A*, Kruse AC*, Xiao K, Reis RI, Tseng WC, Staus DP, Hilger D, Uysal S, Huang LY, Paduch M, Tripathi-Shukla P, Koide A, Koide S, Weis WI, Kossiakoff AA, Kobilka BK, Lefkowitz RJ. Structure of active β-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide. Nature. 497(7447): (2013). 21. Nygaard R, Zou Y, Dror RO, Mildorf TJ, Arlow DH, Manglik A, Pan AC, Liu CW, Fung JJ, Bokoch MP, Thian FS, Kobilka TS, Shaw DE, Mueller L, Prosser RS, Kobilka BK. The Dynamic Process of β(2)-adrenergic Receptor Activation. Cell. 152(3): (2013). 22. Chung KY, Kim TH, Manglik A, Alvares R, Kobilka BK, Prosser RS. Role of detergents in conformational exchange of a G protein-coupled receptor. Journal of Biological Chemistry. 287(43): (2012). 23. Chae PS, Rasmussen SG, Rana RR, Gotfryd K, Kruse AC, Manglik A, Cho KH, Nurva S, Gether U, Guan L, Loland CJ, Byrne B, Kobilka BK, Gellman SH. A new class of amphiphiles bearing rigid hydrophobic groups for solubilization and stabilization of membrane proteins. Chemistry. 18(31): (2012).

4 Aashish Manglik, CV Granier S, Manglik A*, Kruse AC*, Kobilka TS, Thian FS, Weis WI, Kobilka BK. Structure of the δ- opioid receptor bound to naltrindole. Nature. 485(7398): (2012). 25. Manglik A, Kruse AC, Kobilka TS, Thian FS, Mathiesen JM, Sunahara RK, Pardo L, Weis WI, Kobilka BK, Granier S. Crystal structure of the µ-opioid receptor bound to a morphinan antagonist. Nature. 485(7398): (2012). 26. Flentie KN, Qi M, Gammon ST, Razia Y, Lui F, Marpegan L, Manglik A, Piwnica-Worms D, McKinney JS. Stably Integrated luxcdabe for Assessment of Salmonella Invasion Kinetics. Molecular Imaging. 7(5): (2008). Patents 1. Steyaert J, Pardon E, Laeremans T, Kobilka B, Manglik A. Opioid receptor binding agents and uses thereof. European patent application PCT/EP2015/ Kruse, AC, Ring AM, Manglik A, Kobilka, BK. Method for Selecting Agents That Bind to Transmembrane Receptors in a Conformationally-Selective Manner. US patent application PCT/US2014/ Steyaert J, Pardon E., Kobilka B., Ring AM, Kruse A, Manglik A. Muscarinic acetylcholine receptor binding agents and uses thereof. European patent application PCT/EP2014/ Ring AM, Kruse A, Manglik A, Weissman IL, Maute RL, McCraken MN, Gordon S. High affinity PD-1 agents and methods of use. US patent application PCT/US2015/ Shoichet BK, Lin H, Gmeiner P, Manglik A, Kobilka B, Roth BL, Dengler DS. Mu opioid receptor modulators. US patent application 62/190,390 Invited presentations 1. Structural basis of opioid receptor activation. International Narcotics Research Conference. Bath, United Kingdom, July Structural dynamics in G protein-coupled receptor function. Program in Cellular and Molecular Medicine, Boston Children s Hospital and Harvard Medical School. Boston, Massachusetts, July Molecular and structural insights into opioid receptor activation. SENRI Life Science International Symposium, Osaka, Japan, January Structural insights into opioid receptor signaling. Department of Cell Biology and Physiology, Washington University in St. Louis, Missouri, December Protein Engineering and Combinatorial Biology for Structural Characterization of GPCR conformational dynamics. Great Lakes GPCR Retreat. Toronto, Canada. October Structural Dynamics of G Protein-coupled Receptor Activation. British Pharmacological Society: 5 th Focused Meeting on Cell Signalling. University of Leicester, Leicester, United Kingdom, April 2014.

5 Aashish Manglik, CV 5 7. Leveraging Combinatorial Biology Methods to Understand GPCR Function. Keystone Symposia: G Protein-Coupled Receptors, Structural Dynamics and Functional Implications. Snowbird, Utah, April Chasing the Dragon: Structural Insights into Opioid Receptor Function. GPCR Mini-Symposium & LCP Workshop. Tsinghua University, Beijing, China, April 2012.