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Zhang (Cheng) Lab

Lei Wang, PhD

Research interests include the structural mechanisms of several G protein-coupled receptors (GPCRs) that play roles in human metabolic homeostasis, in particular (1) solving structures of vasopressin V2 receptor (V2R), prostaglandin D2 receptor (CRTH2), dopamine receptor and formylpeptide receptor bound with pharmacologically relevant ligands and signaling molecules, (2) performing related molecular studies to understand the pharmacological mechanism of GPCR signaling. Another research interest is using yeast display to develop functional antibodies and engineer proteins to regulate activities of immune receptors that regulating the functions of macrophages and T cells including GPCRs.
 

Cheng Zhang, PhD

My group studies structure, pharmacology and signaling of G protein-coupled receptors (GPCRs) as important cell membrane-embedded receptors. GPCR family has over 700 members. They transduce signals from extracellular signaling molecules to intracellular effectors through conformational changes within the receptors to mediate and regulate a broad spectrum of physiological and pathological processes. GPCRs have been heavily investigated in the pharmaceutical industry, and they constitute 30-40% of current drug targets. My lab utilizes structural biology approaches including X-ray crystallography and cryo-electron microscopy (cryo-EM) and functional studies including ligand-binding assays and cellular signaling assays to explore the molecular mechanisms underlying the signal transduction of GPCRs.

 

Currently, we focus on two groups of GPCRs: 1) the chemotactic GPCRs that recognize peptide and lipid chemoattractants involved in various inflammatory diseases; 2) the GPCRs for small-molecule and peptide neurotransmitters and neuromodulators involved in neurological and psychiatric disorders. We aim to reveal the structural basis for ligand recognition, activation, signaling, allosteric modulation and functional selectivity (biased signaling) of these GPCRs. In addition, we also perform structure-based drug design (SBDD) studies through collaboration and develop new GPCR antibodies as novel therapeutic candidates through combinatorial biology approaches such as yeast display.

Link to our publications:  https://www.ncbi.nlm.nih.gov/myncbi/1Xqbv7vTlyh5w/bibliography/public/

 

https://www.czhanglab.org/

Headshot of Lei Wang, PhD
Lei Wang, PhD
Research Instructor

Headshot of Cheng Zhang, PhD
Cheng Zhang, PhD
Associate Professor

Lei Wang, PhD

Journal Articles

H Liu, RNV Krishna Deepak, A Shiriaeva, C Gati, A Batyuk, H Hu, U Weierstall, W Liu, L Wang, V Cherezov, H Fan and C Zhang. Molecular basis for lipid recognition by the prostaglandin D2 receptor CRTH2. Proc. Natl. Acad. Sci. USA. 118(32) e2102813118, 2021.
 
L Wang, J Xu, S Cao, D Sun, H Liu, Q Lu, Z Liu, Y Du and C Zhang. Cryo-EM structure of the AVP-vasopressin receptor 2-Gs signaling complex. Cell Research 31:932-934, 2021.
 
Y Zhuang, P Xu, C Mao, L Wang, B Krumm, XE Zhou, S Huang, H Liu, X Cheng, X-P Huang, D Sheng, T Xu, Y-F Liu, Y Wang, J Guo, Y Jiang, H Jiang, K Melcher, BL Roth, Y Zhang, C Zhang and HE Xu. Structure of the human D1 and D2 dopamine signaling complexes. Cell 184(4):931-942.e18, 2021.
 
Y Zhuang, H Liu, XE Zhou, RK Verma, P de Waal, W Jang, T-H Xu, L Wang, X Meng, G Zhao, Y Kang, K Melcher, H Fan, N Lambert, HE Xu and C Zhang. Structure of formylpeptide receptor 2-Gi complex reveals insights into ligand recognition and signaling. Nature Communications 14:11(1):885, 2020.
 
Q Xiao, L Wang, S Supekar, T Shen, H Liu, F Ye, JZ Huang, H Fan, Z Wei and C Zhang. Structure of human steroid 5α-reductase 2 with anti-androgen drug finasteride. Nature Communications 11(1): 5430, 2020.
 
L Wang, D Yao, RNV Krishna Deepak, H Liu, Q Xiao, H Fan, W Gong, Z Wei and C Zhang. Structures of the Human PGD2 Receptor CRTH2 Reveal Novel Mechanisms for Ligand Recognition. Molecular Cell 72(1):48-59.e4, 2018.
 
H Liu, HR Kim, RNV Krishna Deepak, L Wang, KY Chung, H Fan, Z Wei and C Zhang. Orthosteric and allosteric action of the C5a receptor antagonists. Nature Structural & Molecular Biology 25(6):472-481, 2018.
 

Cheng Zhang, PhD

Journal Articles

Xing C, Y Zhuang, TH Xu, Z Feng, XE Zhou, M Chen, L Wang, X Meng,Y Xue, J Wang, H Liu, TF McGuire, G Zhao, K Melcher, C Zhang, HE Xu and XQ Xie.  Cryo-EM structure of the human cannabinoid receptor CB2-Gi signaling complex.  Cell 180:645-654.e13, 2020.
Zhuang Y, H Liu, X Edward Zhou, R Kumar Verma, PW de Waal, W Jang, TH Xu, L Wang, X Meng, G Zhao, Y Kang, K Melcher, H Fan, NA Lambert, H Eric Xu and C Zhang.  Structure of formylpeptide receptor 2-Gi complex reveals insights into ligand recognition and signaling.  Nat Commun 11:885, 2020.
Qi X, H Liu, B Thompson, J McDonald, C Zhang and X Li. Structure of human smoothened coupled to a heterotrimeric Gi protein. Nature 571:279-283, 2019.
Masureel M, Y Zou, L-P Picard, E van der Westhuizen, JP Mahoney, JPGLM Rodrigues, TJ Mildorf, RO Dror, DE Shaw, M Bouvier, E Pardon, J Steyaert, RK Sunahara, WI Weis, C Zhang and BK Kobilka.  Structural insights into binding specificity, efficacy and bias of a ß2AR partial agonist.  Nature Chemical Biology 14:1059-1066, 2018.
Wang L, D Yao, RNVK Deepak, H Liu, Q Xiao, H Fan, W Gong, Z Wei and C Zhang. Structures of the human PGD2 receptor CRTH2 reveal novel mechanisms for ligand recognition. Molecular Cell 72:48-59 e4, 2018.
Liu H, HR Kim, RNVK Deepak, L Wang, KY Chung, H Fan, Z Wei and C Zhang. Orthosteric and allosteric action of the C5a receptor antagonists. Nature Structural & Molecular Biology 25:472-481, 2018.
Weichert D, AC Kruse, A Manglik, C Hiller, C Zhang, H Hübner, BK Kobilka and P Gmeiner.  Covalent agonists for studying G protein-coupled receptor activation.  PNAS 111:10744,10748, 2014.
Zocher M, C Bippes, C Zhang and DJ Muller.  Single-molecule force spectroscopy of G-protein-coupled receptors.  Chem Soc REv 42:7801-7815, 2013.
Zhang C, Y Srinivasan, DH Arlow, JJ Fung, D Palmer, Y Zhang, HF Green, A Pandey, RO Dror, DE Shaw, WI Weis, SR Coughlin and BK Kobilka.  High-resolution crystal structure of human protease-activated receptor 1.  Nature 492:387-392, 2012.
Zocher M, C Zhang, SGF Rasmussen, BK Kobilka and DJ Muller.  Cholesterol increases kinetic, energetic, and mechanical stability of the human ß2 adrenergic receptor.  PNAS 109:E3463-E3472, 2012.
Rosenbaum DM, C Zhang, J Lyons, R Holl, D Aragao, DH Arlow, SGF Rasmussen, H Choi, BT DeVee, RK Sunahara, PS Chae, SH Gellman, RO Dror, DE Shaw, WI Weis, M Caffrey, P Gmeiner and BK Kobilka.  Structure and function of an irreversible agonist-ß2 adrenoceptor complex.  Nature 469:236-240, 2011.
Zhang C, L Liu, H Xu, Z Wei, Y Wang, Y Lin and W Gong.  Crystal structures of human IPP isomerase:  New insights into the catalytic mechanism.  J Mol Biol 366:1437-1446, 2007.