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Name:
Zhao Qiang
Education:
Ph.D

Positions:
Principal Investigator
Academic title:
Professor
Phone:
021-20231000-1785
Fax:
20231966
E-mail:
zhaoq@simm.ac.cn
Personal Website:
Postal Code:
201203
Mailing Address:
501 Haike Road, Zhang Jiang Hi-Tech Park, Pudong, Shanghai, P.R.China. 201203
Resume:

The research focus of Dr. Zhao is mainly on understanding the relationship between protein structure and function, and the mechanism of recognition mechanisms between protein molecules and substrates. During his Ph.D. study he solved the crystal structure of human Spindlin1, a newly discovered cancer related protein, and then speculated and proved its function from the structure. After expending his work to membrane protein field, Dr. Zhao and co-workers solved the structure of Dopamine receptor D3DR, based on which they identified a second pocket for ligand binding. In 2011, Dr. Zhao moved back Shanghai and started his own group, and start working on solving the membrane protein structures involved in human diseases. His research focus is mainly on the important GPCRs involved in the cardiovascular diseases and neurological diseases. The structure determination of such receptors will shed a light on future research direction of high selectivity agents.

EDUCATION
08/31/1998 – 07/12/2002 Tsinghua University
09/01/2002 – 02/05/2007 Tsinghua University

WORK EXPERIENCE
04/02/2007 – 07/19/2011 The Scripps Research Institute
07/21/2011 –                    Shanghai Institute of Materia Medica, CAS


Research Directions

Dr. Zhao's research group is targeting on solving high resolution structures of diseases related G-protein coupled receptors (GPCRs) and structure based drug design with the following focuses:
1. Development and application of new technologies for solving GPCR structures;
2. Structural study and signaling mechanism study on GPCRs related to cardiovascular/autoimmune/metabolic disease;
3. Structural study of GPCRs with downstream signaling molecules.


Social Titles

Awards & Honors

05/2014 May 4th lab of Young Fellow of Shanghai


Achievements

The research of Zhao lab is mainly focused on determining the high resolution structures of GPCRs and the structure-function relationship behind these structures. The Zhao lab is trying to apply their results into biomedical research and help the optimization of current drugs or the discovery of new drugs. 

In the past 3 years since the lab was founded, they have solved several GPCR structures and published papers on the high impact journals such as Nature and Science. These achievements are illustrated as below: 

1.The structural studies of P2Y12R 
Purinergic P2Y receptors belong to the metabotropic P2Y purinergic GPCRs that stimulated by nucleotides. These receptors play crucial roles in inflammation, cancer and cardiovascular diseases. There are two distinct P2Y receptors for ADP expressed on platelet: the Gq-coupled P2Y1R and the Gi-coupled P2Y12R. They both contribute to collagen-induced platelet microparticle formation in whole blood and the formation of platelet-leukocyte aggregates. 

Several generations of P2Y12R-targetting antithrombotic drugs have been developed on the market for its critical function role in platelet aggregation, such as clopidogrel and prasugrel that need to be metabolized before covalently binding to the P2Y12R or ticagrelor that are directly act on P2Y12R. However, clinical experience revealed certain limitations of these drugs (long half-life or strong side effects), suggesting an unfulfilled medical need in developing a new generation of P2Y12R inhibitors, which was severely limited by lacking of receptor structure and biochemical information. 

In 2013, the Zhao lab solved the crystal structure of P2Y12R in an inactive state in complex with antagonist AZD1283, and the paper was published on Nature, May 2014. The P2Y12R structure contains typical seven transmembrane helices, and was characterized by a straight helix V. Helix VI of P2Y12R also adopts an unexpected conformation. These unique features suggest that the residue interaction network within P2Y12R might be different, which made this receptor distinct from all other known class A GPCR structures. The ligand AZD1283 binds to P2Y12R in a pocket composed by helices III, IV, V, VI and VII, which is distinct from and adjacent to the traditional ligand binding pocket of receptors in the α, β and γ groups. However, the same binding pocket was also observed in the structure of PAR1 that also belongs to the δ group, indicating that this might be a general structural feature of δ group GPCRs. The fact that binding pockets are composed by different helices in the receptors explains how the recognition of so many different chemicals was achieved by a similar seven transmembrane helix bundle. 

There are two pockets exist in P2Y12R: pocket 1 is composed of helices III - VII, forming the binding site of AZD1283; while pocket 2 consists of helices I-III and VII and is not occupied in the structure. Docking assays suggested that pocket 1 is more likely to be the binding site for the reversible ligand, while pocket 2 is the more preferable site for the pro-drugs. Agreeing with the docking results, , only one disulfide bond is observed, which is between C17 and C2707.25 in the antagonist-bound structure, while the conserved disulfide bond between C973.25 and C175ECL2 is very flexible and not modeled. A labile conserved disulfide makes the side chain of C973.25 more likely to exist as free thiol group than the other GPCRs, and this explains the absolute selectivity of the active metabolites of pro-drugs and the thiol-reactive reagents for the P2Y12R; to date, there have been no reports that they exhibit detectable binding to any other receptors. 

Based on the antagonist-bound structure, the Zhao lab further solved the crystal structures of P2Y12R in complex with a full agonist (2MeSADP) at 2.5 Å and structure with a potential partial agonist (2MeSATP) at 3.1 Å. The paper was also accepted by Nature, and was published back to back with the antagonist paper on the same issue of May 1st, 2014.  

Notably, in both agonist-bound and antagonist-bound structures, helix V assumes a similar straight and tilted conformation, suggesting that it is a genuine feature in the P2Y12R. The helix VIII of agonist-bound P2Y12R is partially disordered and is not determined owing to weak electron density, which might due to the binding of agonist. 

The overall structure of P2Y12R bound to the agonist 2MeSADP is significant different from that of P2Y12R bound to the antagonist AZD1283. The agonist-bound P2Y12R structure undergoes dramatic changes in the extracellular side. The largest difference is 10 Å and 5 Å inward movements of helices VI and VII, respectively. This is for the first time that the large scale conformational changes of extracellular side in the agonist-bound GPCR structures is observed. As a result, ECL3 that connects helices VI and VII moves towards the receptor core. Interestingly, comparing to the dramatic structural changes observed in the extracellular side, the structural change of the intracellular side is much smaller. No detectable changes are induced for the peptide backbone in helices I, II, III, IV and V, while only small structural changes of helices VI and VII in the intracellular part were observed. Therefore, we propose that the P2Y12R-2MeSADP complex is more likely in an intermediate conformation which is referred as agonist-bound inactive state, rather than a full active conformation. 

The agonist 2MeSADP binding pocket is composed of residues from helices III, IV, V, VI and VII, which is same as AZD1283 binding pocket, even though they are only partially overlapped. ECL2 (residues163-181), which cannot be modeled in the structure of P2Y12R bound to the antagonist AZD1283, covers the extracellular part as a “lid” for ligand binding. This feature suggests that the ECL2 could have a role in ligand recognition or activation. The 2MeSADP binds to P2Y12R in a very different orientation, as compared to AZD1283. The 2MeSADP is oriented perpendicular to the membrane plane, instead of a parallel orientation observed for AZD1283. R933.21, which interacts in β-phosphate, is not predicted to participate ligand binding by any biochemical data. In addition, three water molecules were also observed between R19 (N terminus) and β-phosphate. 

The structure of the agonist-bound P2Y12R with a comparison of antagonist-bound P2Y12R reveals an unanticipated large scale extracellular rearrangement, offering a new view of high plasticity of the extracellular region in the P2Y12R. This is a feature that has not been predicted or observed in any GPCR before, and the plasticity of GPCRs brings new clues for structure based drug design. 

2.The structural studies of CCR5 
In collaboration with Dr. Beili Wu’s group at SIMM, they also solved the crystal structure of chemokine receptor CCR5 in complex with anti-HIV drug maraviroc. The paper was published on Science in 2013. 

Chemokine receptor CCR5, together with another chemokine receptor CXCR4, serve as co-receptors for the HIV virus entry. By comparing the crystal structure of CCR5 and CXCR4, structural evidences of how different receptors are recognized by the glycoprotein GP120 of the virus. In addition, multiple struct   ural features pointed out that the CCR5-maraviroc complex structure adopts inactive conformation.  Based on this, a new allosteric inhibition mechanism was proposed. 

Together with several other groups in SIMM, we performed structural based drug discovery and found a drug that is much more potent than the current drug maraviroc. This drug lead is currently in the preclinical studies and will move forward in the near future. 


Grants & Research Projects

1.973, Ministry of Science and Technology (MOST), China Structural and functional studies and ligand screenings of important GPCRs, Sub-project Leader, 2012.1-2016.12
2.Shanghai Institute of Materia Medica and Chinese Academy of Sciences, “Hundred Talents” Start-up Package, Project Leader, 2011.7-2015.12
3.NIH R01, Molecular Mechanism of HIV Entry Mediated by Chemokine Receptor CCR5, Project Leader, 2012.2-2017.1
4.National Science and Technology Major Project, Ministry of Science and Technology (MOST), China GPCR Structure and Function-based Drug Discovery, Participant, 2013.1-2015.12
5.National Science and Technology Major Project, Ministry of Science and Technology (MOST), China, Key Technology Development and Platform Construction in GPCR Structure and Function-based Drug Discovery, Participant, 2012.1-2015.12
6.Interactional Collaboration and Communication Project, National Natural Science Foundation of China, Protein Structure-based Anti-HIV Drug Discovery, Participant, 2012.1-2012.12
7.Mianshang Project, National Natural Science Foundation of China, Structural and ligand binding studies of human purinergic receptors, Project Leader, 2014.1-2017.12
8.Mianshang Project, National Natural Science Foundation of China, Expression and ligand screening of Neurokinin receptor 1, Project Leader, 2012.1-2015.12


Pubilcations

(2009.1.1- )
1. Chien E, Liu W, Zhao Q, Katritch V, Han GW, Hanson M, Shi L, Newman A, Javitch J, Cherezov V, Stevens R*. Structure of the Human Dapamine D3 Receptor in Complex with a D2/D3 Selective Antagonist. Science. 2010; 330(6007): 1091-5.

2. Qiang Zhao*, Beili Wu. Ice breaking in GPCR structural biology. Acta Pharmacol Sin. 2012; 33(3): 324-334.

3. Yang N, Wang W, Wang Y, Wang M, Zhao Q, Rao Z, Zhu B, Xu RM*.Distinct mode of methylated lysine-4 of histone H3 recognition by tandem tudor-like domains of Spindlin1. Proc Natl Acad Sci U S A. 2012; 109(44):17954-9.

4. Qiuxiang Tan, Ya Zhu, Jian Li, Zhuxi Chen, Gye Won Han, Irina Kufareva, Tingting Li, Limin Ma, Gustavo Fenalti, Jing Li, Wenru Zhang, Xin Xie, Huaiyu Yang, Hualiang Jiang, Vadim Cherezov, Hong Liu, Raymond C. Stevens, Qiang Zhao, Beili Wu*. Structure of the CCR5 chemokine receptor-HIV entry inhibitor maraviroc complex. Science. 2013; 341: 1387-1390.

5. Lan Zhu, Qiang Zhao & Beili Wu*. Structure-based studies of chemokine receptors. Curr Opin Struct Biol. 2013; 23: 539-546.

6. Jin Zhang, Kaihua Zhang, Zhan-Guo Gao, Silvia Paoletta, Dandan Zhang, Gye Won Han, Tingting Li, Limin Ma,
Wenru Zhang, Christa E. Müller, Huaiyu Yang, Hualiang Jiang, Vadim Cherezov, Vsevolod Katritch, Kenneth A. Jacobson, Raymond C. Stevens, Beili Wu* & Qiang Zhao*. Agonist-bound structure of the human P2Y12 receptor. Nature. 2014; 509: 119-122.

7. Kaihua Zhang, Jin Zhang, Zhan-Guo Gao, Dandan Zhang, Lan Zhu, Gye Won Han, Steven M. Moss, Silvia Paoletta, Evgeny Kiselev, Weizhen Lu, Gustavo Fenalti, Wenru Zhang, Christa E. Müller, Huaiyu Yang, Hualiang Jiang,
Vadim Cherezov, Vsevolod Katritch, Kenneth A. Jacobson, Raymond C. Stevens, Beili Wu & Qiang Zhao*. Structure of the human P2Y12 receptor in complex with an antithrombotic drug. Nature. 2014; 509: 115-118.