Aashish Manglik, MD, PhD

Assistant Professor

Department of Pharmaceutical Chemistry

[email protected]

Phone: +1 415 502-3744

1700 4th St, Rm 508C

UCSF Box 2550

San Francisco, CA 94158

United States

Links

Manglik Lab

UCSF Profiles

What I do

I am a physician-scientist interested in understanding how the human body senses and responds to external stimuli. My research focuses on the largest group of drug targets in the human body, the G protein coupled receptors. We aim to understand the most basic principles of these receptors in order to develop new medications that are both more effective and have decreased side effects.

Departmental research area

chemical biology and medicinal chemistry

protein and cellular engineering

My research expertise

G-protein-coupled receptors (GPCRs), structural biology, signaling, protein dynamics

Degrees

MD, Medicine, Stanford University School of Medicine, 2016

PhD, Biophysics, Stanford University, 2014

BA, Chemistry and Biology, Washington University, 2008

Research keywords

G protein-coupled receptor, GPCR, opioid receptors, signaling, structural biology, protein biophysic, Receptors, G-Protein-Coupled, Receptors, Adrenergic, beta-2, Single-Domain Antibodies, Receptors, Opioid, mu, Smoothened Receptor

1.	Young Investigator Award, International Narcotics Research Conference, 2017
2.	Director's Early Independence Award, National Institutes of Health, 2016-2021
3.	30 under 30, Scientific American, 2013
4.	Spector Award, Washington University in St. Louis, 2008

Publications

Manglik A. Molecular Basis of Opioid Action: From Structures to New Leads. Biol Psychiatry. 2019 Sep 12.

Deshpande I, Liang J, Hedeen D, Roberts KJ, Zhang Y, Ha B, Latorraca NR, Faust B, Dror RO, Beachy PA, Myers BR, Manglik A. Smoothened stimulation by membrane sterols drives Hedgehog pathway activity. Nature. 2019 07; 571(7764):284-288.

Maeda S, Koehl A, Matile H, Hu H, Hilger D, Schertler GFX, Manglik A, Skiniotis G, Dawson RJP, Kobilka BK. Development of an antibody fragment that stabilizes GPCR/G-protein complexes. Nat Commun. 2018 09 13; 9(1):3712.

Livingston KE, Mahoney JP, Manglik A, Sunahara RK, Traynor JR. Measuring ligand efficacy at the mu-opioid receptor using a conformational biosensor. Elife. 2018 06 22; 7.

Koehl A, Hu H, Maeda S, Zhang Y, Qu Q, Paggi JM, Latorraca NR, Hilger D, Dawson R, Matile H, Schertler GFX, Granier S, Weis WI, Dror RO, Manglik A, Skiniotis G, Kobilka BK. Structure of the µ-opioid receptor-Gi protein complex. Nature. 2018 06; 558(7711):547-552.

Stoeber M, Jullié D, Lobingier BT, Laeremans T, Steyaert J, Schiller PW, Manglik A, von Zastrow M. A Genetically Encoded Biosensor Reveals Location Bias of Opioid Drug Action. Neuron. 2018 06 06; 98(5):963-976.e5.

Staus DP, Wingler LM, Choi M, Pani B, Manglik A, Kruse AC, Lefkowitz RJ. Sortase ligation enables homogeneous GPCR phosphorylation to reveal diversity in ß-arrestin coupling. Proc Natl Acad Sci U S A. 2018 04 10; 115(15):3834-3839.

McMahon C, Baier AS, Pascolutti R, Wegrecki M, Zheng S, Ong JX, Erlandson SC, Hilger D, Rasmussen SGF, Ring AM, Manglik A, Kruse AC. Yeast surface display platform for rapid discovery of conformationally selective nanobodies. Nat Struct Mol Biol. 2018 03; 25(3):289-296.

Manglik A, Kruse AC. Structural Basis for G Protein-Coupled Receptor Activation. Biochemistry. 2017 10 24; 56(42):5628-5634.

Manglik A, Kobilka BK, Steyaert J. Nanobodies to Study G Protein-Coupled Receptor Structure and Function. Annu Rev Pharmacol Toxicol. 2017 01 06; 57:19-37.

Manglik A, Lin H, Aryal DK, McCorvy JD, Dengler D, Corder G, Levit A, Kling RC, Bernat V, Hübner H, Huang XP, Sassano MF, Giguère PM, Löber S, Scherrer G, Kobilka BK, Gmeiner P, Roth BL, Shoichet BK. Structure-based discovery of opioid analgesics with reduced side effects. Nature. 2016 09 08; 537(7619):185-190.

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 G-protein-coupled receptor activation. Nature. 2016 07 21; 535(7612):448-52.

DeVree BT, Mahoney JP, Vélez-Ruiz GA, Rasmussen SG, 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. 2016 07 07; 535(7610):182-6.

Schmidt HR, Zheng S, Gurpinar E, Koehl A, Manglik A, Kruse AC. Crystal structure of the human s1 receptor. Nature. 2016 Apr 28; 532(7600):527-30.

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. 2016 Jan; 72(Pt 1):2-11.

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. Proc Natl Acad Sci U S A. 2015 Nov 24; 112(47):E6506-14.

Aashish Manglik, Tae Hun Kim, Matthieu Masureel, Christian Altenbach, Zhongyu Yang, Daniel Hilger, Michael T. Lerch, Tong Sun Kobilka, Foon Sun Thian, Wayne L. Hubbell, R. Scott Prosser, Brian K. Kobilka. Structural Insights into the Dynamic Process of ß2-Adrenergic Receptor Signaling. Cell. 2015 Sep 1; 162(6):1431.

Sounier R, Mas C, Steyaert J, Laeremans T, Manglik A, Huang W, Kobilka BK, Déméné H, Granier S. Propagation of conformational changes during µ-opioid receptor activation. Nature. 2015 Aug 20; 524(7565):375-8.

Huang W, Manglik A, Venkatakrishnan AJ, Laeremans T, Feinberg EN, Sanborn AL, Kato HE, Livingston KE, Thorsen TS, Kling RC, Granier S, Gmeiner P, Husbands SM, Traynor JR, Weis WI, Steyaert J, Dror RO, Kobilka BK. Structural insights into µ-opioid receptor activation. Nature. 2015 Aug 20; 524(7565):315-21.

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. SIGNAL TRANSDUCTION. Structural basis for nucleotide exchange in heterotrimeric G proteins. Science. 2015 Jun 19; 348(6241):1361-5.

Manglik A, Kim TH, Masureel M, Altenbach C, Yang Z, Hilger D, Lerch MT, Kobilka TS, Thian FS, Hubbell WL, Prosser RS, Kobilka BK. Structural Insights into the Dynamic Process of ß2-Adrenergic Receptor Signaling. Cell. 2015 May 21; 161(5):1101-1111.

Ye L, Larda ST, Frank Li YF, Manglik A, Prosser RS. A comparison of chemical shift sensitivity of trifluoromethyl tags: optimizing resolution in ¹?F NMR studies of proteins. J Biomol NMR. 2015 May; 62(1):97-103.

Li L, Homan KT, Vishnivetskiy SA, Manglik A, Tesmer JJ, Gurevich VV, Gurevich EV. G Protein-coupled Receptor Kinases of the GRK4 Protein Subfamily Phosphorylate Inactive G Protein-coupled Receptors (GPCRs). J Biol Chem. 2015 Apr 24; 290(17):10775-90.

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. Proc Natl Acad Sci U S A. 2014 Dec 02; 111(48):17122-7.

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 U S A. 2014 Jul 22; 111(29):10744-8.

Manglik A, Kobilka B. The role of protein dynamics in GPCR function: insights from the ß2AR and rhodopsin. Curr Opin Cell Biol. 2014 Apr; 27:136-43.

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. 2013 Dec 05; 504(7478):101-6.

Kruse AC, Manglik A, Kobilka BK, Weis WI. Applications of molecular replacement to G protein-coupled receptors. Acta Crystallogr D Biol Crystallogr. 2013 Nov; 69(Pt 11):2287-92.

Ring AM, Manglik A, Kruse AC, Enos MD, Weis WI, Garcia KC, Kobilka BK. Adrenaline-activated structure of ß2-adrenoceptor stabilized by an engineered nanobody. Nature. 2013 Oct 24; 502(7472):575-579.

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. J Am Chem Soc. 2013 Jun 26; 135(25):9465-74.

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 ß-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide. Nature. 2013 May 02; 497(7447):137-41.

Pil Seok Chae, Søren G. F. Rasmussen, Rohini R. Rana, Kamil Gotfryd, Andrew C. Kruse, Aashish Manglik, Kyung Ho Cho, Shailika Nurva, Ulrik Gether, Lan Guan, Claus J. Loland, Bernadette Byrne, Brian K. Kobilka, Samuel H. Gellman. Corrigendum: A New Class of Amphiphiles Bearing Rigid Hydrophobic Groups for Solubilization and Stabilization of Membrane Proteins. Chemistry - A European Journal. 2013 Apr 15; 19(16):4964-4964.

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 ß(2)-adrenergic receptor activation. Cell. 2013 Jan 31; 152(3):532-42.

Chung KY, Kim TH, Manglik A, Alvares R, Kobilka BK, Prosser RS. Role of detergents in conformational exchange of a G protein-coupled receptor. J Biol Chem. 2012 Oct 19; 287(43):36305-11.

Pil Seok Chae, Søren G. F. Rasmussen, Rohini R. Rana, Kamil Gotfryd, Andrew C. Kruse, Aashish Manglik, Kyung Ho Cho, Shailika Nurva, Ulrik Gether, Lan Guan, Claus J. Loland, Bernadette Byrne, Brian K. Kobilka, Samuel H. Gellman. Inside Cover: A New Class of Amphiphiles Bearing Rigid Hydrophobic Groups for Solubilization and Stabilization of Membrane Proteins (Chem. Eur. J. 31/2012). Chemistry - A European Journal. 2012 Jul 27; 18(31):9434-9434.

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. 2012 Jul 27; 18(31):9485-90.

Granier S, Manglik A, Kruse AC, Kobilka TS, Thian FS, Weis WI, Kobilka BK. Structure of the d-opioid receptor bound to naltrindole. Nature. 2012 May 16; 485(7398):400-4.

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. 2012 Mar 21; 485(7398):321-6.

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. Mol Imaging. 2008 Sep-Oct; 7(5):222-33.