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Home > Faculty > SUSTech Faculty Finder > Zhang Hongmin

Faculty

Zhang Hongmin


Associate Professor

Department of Biolgoy

0755-88018419

zhanghm@sustc.edu.cn

Research Interests:

The main research field in Dr Zhang’s lab focuses on structural biology studies using X-ray crystallography. The general procedure (shown below) for structural biology starts from gene cloning and protein purification. And then we need to get crystals for the collection of X-ray diffraction data. Following the phase determination by various methods, we can then build models and refine the structure with a computer. The last step is the analysis of structures to find clues to explain functional studies or predict potential functions for further verification.

There are two main research directions in Dr Zhang’s lab. One is the study of the interactions between macromolecules involved in cellular microenvironment and the other is the study of pathogenic mechanism of various emerging pathogens as well as the structure-based design and screening of small molecule inhibitors.

 

◆The interaction study of macromolecules in cellular microenvironment

Cells are the basic unit of all life activities. Any physiological or pathological conditions in human can be deduced to certain cellular activities which are largely influenced by their internal and external microenvironments. In physiological conditions, cells sense and transduce signals from extracellular matrix or other cells to the cytosol where signals can be further transmitted to other cellular components via a serial of interactions among macromolecules. Eventually cells respond to the stimuli at proper degree. Vice versa, signals in cells can also be transmitted via a similar pathway to extracellular matrix or other cells. However, in pathological conditions, signal transduction can be improperly processed at any step of that pathway, which usually results in illness. Using structural biology methods, we will study the interactions of macromolecules involved in cellular signal transductions to provide better understanding of these processes and also potential therapeutic strategy.

 1.Signal transduction of integrins during cell adhesion

Integrins play a central role during the adhesion of cell to cell and cell to extracellular matrix. It can transduce signals bidirectionally, i.e. ‘out-in’ signaling and ‘inside-out’ signaling. It is already known that a lot of cellular proteins can bind the cytoplasmic tail of integrins and these proteins transduce the activating signal from integrins to other cellular proteins or cytoskeleton. One example of these proteins, ILK, plays an important role during cell adhesion (shown below). We will study the interactions among these proteins to further understand the signal transduction from integrins.

2.Proteins involved in Calcium signaling

Calcium (Ca2+) signals are crucial for the control of a broad range of cellular functions, such as secretion, excitation, contraction, motility, metabolism, transcription, growth, cell division and apoptosis. Numerous pumps, channels and cellular proteins have been found to comprise the machinery for generating cellular Ca2+ signals. However, it is less understood how these proteins are coordinated to generate temporally and spatially precise Ca2+ signals to control individual cell functions. The figure below shows a cell in resting (left panel) as well as in activating states (right panel). During signal transduction process, a lot of proteins are involved to regulate the sequential activation and de-activation of Ca2+ signals. We will study the interactions among these proteins to reveal how Ca2+ signaling is regulated.

◆Pathogenic mechanism of emerging pathogens and structure-based inhibitor design and screening

  There are lots of pathogens in our environment, including bacteria, fungi and viruses. Because of their rapid mutation ability, they can easily resist to previous effective therapeutics, raising great challenge to our healthcare system. Better understanding of the pathogenic mechanism of these emerging pathogens may provide solid evidence for the design of more promising therapeutics. In this process, we will use structural biology methods to study the interactions between pathogens and human cells, especially proteins involved in the infection and clearance processes. We will elucidate the pathogenic mechanism at atomic level and provide clear information for therapeutics design. The interaction between these small molecules and proteins can be measured and compared for further optimization to yield potential lead drugs. Below are three projects we have done or still on-going.

1.‘super-bug’ protein NDM-1

NDM-1 is a metallo-beta-lactamase. It can hydrolyze almost all beta-lactam antibiotics including ampicillin, carbapenem family antibiotics. Carbapenems are the mainstay for the treatment of antibiotic-resistant bacteria. So bacteria containing NDM-1 gene pose a great threat to our healthcare system. We solved the first high resolution crystal structure of NDM-1 in complex with its hydrolysis product of ampicillin. Shown below in panel A is the structure of ampicillin and hydrolyzed ampicillin. Shown in panel B is NDM-1 enclosing a hydrolyzed ampicillin at its active groove formed by two loops (L3 loop in red and L10 loop in gold).

2.Nucleoprotein of influenza H5N1

Influenza viruses mutate very rapidly, rendering the in time production of specific vaccines impossible. The genome of influenza virus subtype A encodes 12 different proteins, including two serotype-determinant proteins HA and NA which are highly variable. Nucleoprotein, also encoded by virus genome, is responsible for the transcription, translation and assembling of viruses. Because of its high conservation among different serotypes, it is considered a promising drug target. We determined the first crystal structure of H5N1 nucleoprotein and made a model showing how nucleoprotein might enclose RNA genome (figure shown below), providing structural basis for elucidating the functions of nucleoprotein and also the design of small molecule inhibitors.

  1. 3.Virulence factors in Aspergillus fumugatus

  2.  Aspergillus fumugatus is the cause of invasive aspergillosis, the most globally important and fatal mold infections in immune-compromised patients with cancer, AIDS, bone marrow and solid organ transplant. Despite of its medical importance, little is known about its pathogenesis mechanism. Our collaborators have found that Aspergillus fumugatus can secrete a kind of proteins into the blood of infected patients. Using microbiological, cellular and molecular biology methods, they have got strong evidence showing that this kind of proteins should be the virulence factor of Aspergillus fumugatus. We determined the crystal structure of this protein and identified a fatty acid molecule, arachidonic acid, bound in the central groove of this protein. Arachidonic acid is the precursor of many lipid molecules for activating the innate immune response. Hence, Aspergillus fumugatus may suppress the immune response of patients by depletion of arachidonic acids through secretion of this kind of fatty acid binding proteins. Shown below is the crystal structure with arachidonic acid bound in the central groove. The electron density for arachidonic acid is shown in green mesh.

Professional Experience:

2013~now, Associate professor, South University of Science and Technology of China
2008~2013, Research assistant professor, Department of Physiology, the University of Hong Kong

2004~2008, postdoctoral fellow, Dana-Farber Cancer Institute, Harvard Medical School

 

Educational Background:

◆ 1999~2004, PhD in Biology, School of life sciences, University of Science and Technology of China

◆ 1995~1999, Bachelor in Life Sciences, School of life sciences, University of Science and Technology of China

 

Honors & Awards:

◆ 2014 Overseas high-caliber personnel in Shenzhen (Peacock plan B)

 

Selected publications:

◆Google Scholar link: http://scholar.google.com/citations?user=SA0X0OkAAAAJ

Protein-complex structure completion using IPCAS (Iterative Protein Crystal structure Automatic Solution),Weizhe Zhang, Hongmin Zhang, Tao Zhang, Haifu Fan and Quan Hao,2015,Acta Cryst. D71, 1487–1492
“Anion clamp” allows flexible protein to impose coordination geometry on metal ions. M Wang, TP Lai, L Wang, H Zhang, N Yang, PJ Sadler, H Sun, Chemical Communications 2015, 51 (37), 7867-7870
Cyclic Adenosine 5'-Diphosphate Ribose Analogs without a "Southern" Ribose Inhibit ADP-ribosyl Cyclase-Hydrolase CD38. Swarbrick JM, Graeff R, Zhang H, Thomas MP, Hao Q, Potter BV. J Med Chem. 2014 Oct 1.
Crystallographic phasing with NMR models: an envelope approach. Zhang W, Zhang T, Zhang H, Hao Q. Acta Crystallogr D Biol Crystallogr. 2014 Jul;70(Pt 7):1977-82.
Hongmin Zhang, Richard Graeff, Hon Cheung Lee, and Quan Hao (2013) Crystal Structures of Human CD38 in Complex with NAADP and ADPRP Messenger Vol. 2, 44-53
Nan Yang, Hongmin Zhang, Minji Wang, Quan Hao and hongzhe Sun (2012) Iron and bismuth bound human serum transferrin reveals a partially-opened conformation in the N-lobe. Scientific Report , 2:999. doi: 10.1038/srep00999. Epub 2012 Dec 19
Kwong, A. K.; Chen, Z.; Zhang, H.; et al. (2012) Catalysis-based inhibitors of the calcium signaling function of CD38. Biochemistry Volume: 51 Issue: 1 Pages: 555-64 (co-first)
Zhang, H.; Wang, J. H. (2012) Protein expression and purification of integrin I domains and IgSF ligands for crystallography. Methods Mol Biol Volume: 757 Pages: 101-10 (corresponding)
Ng, A. K.; Lam, M. K.; Zhang, H.; et al. (2012) Structural basis for RNA-binding and homo-oligomer formation by influenza B virus nucleoprotein. J Virol 86(12): 6758-67
Zhou, Y.; Zhang, H.; He, B.; et al. (2012) The Bicyclic Intermediate Structure Provides Insights into the Desuccinylation Mechanism of Human Sirtuin 5 (SIRT5) J Biol Chem Volume: 287 Issue: 34 Pages: 28307-14
Zhou, B.; Chen, Q.; Mallis, R. J.; Zhang, H.; et al. (2011) A Conserved Hydrophobic Patch on Vβ Domains Revealed by TCRβ Chain Crystal Structures: Implications for Pre-TCR Dimerization. Front Immunol Volume: 2 Pages: 5
Zhang H, Hao Q. (2011) Crystal structure of NDM-1 reveals a common {beta}-lactam hydrolysis mechanism. FASEB J. Volume: 25 Issue: 8 Pages: 2574-2582 (co-corresponding)
Zhao YJ, Zhang HM, Lam CM, Hao Q, Lee HC. (2011) Cytosolic CD38 protein forms intact disulfides and is active in elevating intracellular cyclic adp-ribose. J Biol Chem. 286(25):22170-7.
Zhang H, Graeff R, Chen Z, Zhang L, Zhang L, Lee H, Hao Q. (2011) Dynamic conformations of the CD38-mediated NAD cyclization captured in a single crystal. J Mol Biol. 405(4):1070-8.
Zhang H, Liu JH, Yang W, Springer T, Shimaoka M, Wang JH. (2009) Structural basis of activation-dependent binding of ligand-mimetic antibody AL-57 to integrin LFA-1. Proc Natl Acad Sci U S A. 106(43):18345-50.
Zhang H, Astrof NS, Liu JH, Wang JH, Shimaoka M. (2009) Crystal structure of isoflurane bound to integrin LFA-1 supports a unified mechanism of volatile anesthetic action in the immune and central nervous systems. FASEB J. 23(8):2735-40.
Zhang H, Casasnovas JM, Jin M, Liu JH, Gahmberg CG, Springer TA, Wang JH. (2008) An unusual allosteric mobility of the C-terminal helix of a high-affinity alpha L integrin I domain variant bound to ICAM-5. Mol. Cell. 31(3):432-7.
Ng AK, Zhang H, Tan K, Li Z, Liu JH, Chan PK, Li SM, Chan WY, Au SW, Joachimiak A, Walz T, Wang JH, Shaw PC. (2008) Structure of the influenza virus A H5N1 nucleoprotein: implications for RNA binding, oligomerization, and vaccine design. FASEB J. 22(10):3638-47.
Sun JS, Zhang QR, Zhang TY, Zhu ZL, Zhang HM, Teng MK, Niu LW, Xu WH (2005) Developmental expression of FXPRLamide neuropeptides in peptidergic neurosecretory cells of diapause- and nondiapause-destined individuals of the cotton bollworm, Helicoverpa armigera, Gen Comp Endocrinol.  141(1): 48-57.
Zhang H, Yang Q, Sun M, Teng M, Niu L. (2004) Hydrogen peroxide produced by two amino acid oxidases mediates antibacterial actions. J. Microbiol. 42(4):336-9.
Zhang H, Teng M, Niu L, Wang Y, Wang Y, Liu Q, Huang Q, Hao Q, Dong Y, Liu P. (2004) Purification, partial characterization, crystallization and structural determination of AHP-LAAO, a novel L-amino-acid oxidase with cell apoptosis-inducing activity from Agkistrodon halys pallas venom. Acta Crystallogr D Biol Crystallogr. 60(Pt 5):974-7

 

Other Info:

◆ Dr Zhang’s lab is recruiting postdoctoral fellow. Anyone with qualified molecular biology, biochemistry or chemical biology expertise and also passion for scientific research are invited to submit a CV to Dr Zhang.

 

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