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Zhen Zhang, Ph.D. Baylor College of Medicine Department: Postdoc Research Scientist, Columbia University Address: Biochem & Mol Biophy Rm 204, Black Building 650 West 168th St. New York NY 10032 Phone: 212-305-1046 Fax: 212-305-7379 Email: zz2121@columbia.edu Web:

Education

B.S. Physical Chemistry, Jilin University - Changchun, China (1995)
M.S. Structural Chemistry, Peking University - Beijing, China (1999)
Ph.D., Structural and Computational Biology and Molecular Biophysics (2004)
Postdoc Research Scientist, Columbia University

Honors

Best Poster: CMB and SCBMB Research Conference (2001)

Poster Award: 9th Structural Biology Symposium (2004)

Research Topic

Protein-protein interactions and protein engineering

Research Description

Protein-protein interactions play a significant role in many cellular processes. Protein binding surfaces exhibit specific chemical and geometric characteristics that determine affinity and specificity for binding targets. The interface between four beta-lactamases (TEM-1, SME-1, SHV-1 and Bla1) and beta-lactamase inhibitory protein (BLIP) is being used as a model system to understand the determinants of binding affinity and specificity in a protein-protein interface. beta-Lactamases hydrolyze beta-lactam antibiotics resulting in bacterial drug resistance. BLIP is able to bind and inhibit several b-lactamases with a wide range of affinities. Alanine scanning mutagenesis was carried out to identify the sequence requirements of BLIP for binding all four target enzymes. Two patches dominated by aromatic residues were found to make important contributions to binding affinity. One patch is surrounded by several hydrophilic residues to occlude solvent from the hotspot as seen in many other protein-protein interactions. The other patch, however, is unusual because it retains some solvent accessibility, which suggests that hydrophilic ring is not a necessary condition for a hotspot. Three regions in BLIP, including two loops that insert into the active pocket of TEM-1, play significantly different roles when binding to different target enzymes and so are defined as specificity determinants. Both Vdw¡¯s interaction and polar interaction play a role in the interaction of specificity determinants. Based on the binding data, five double alanine mutants were constructed to examine the cooperativity of interactions between amino acid residues important for binding. The results of the inhibition assays of the double mutants indicate both synergistic and antagonistic effects between alanine mutants, which suggests cooperative interactions between these residues in the binding interface. Protein engineering based on the research successfully constructs double mutants of BLIP with great specificity change when binding to different enzymes. Preliminary data of drug design using phage display and peptide array indicate that the knowledge gained from the research can be used to guide the study of novel inhibitor design of beta-lactamases.

Selected Publications

• Adediran SA, Zhang Z, Nukaga M, Palzkill T, Pratt RF. The d-Methyl Group in beta-Lactamase Evolution: Evidence from the Y221G and GC1 Mutants of the Class C beta-Lactamase of Enterobacter cloacae P99.(2005) Biochemistry. 44(20):7543-7552
• Zhang Z. and Palzkill TG. (2004). Dissecting the protein-protein interface between beta-lactamase inhibitory protein and class A beta-lactamases. J. Biol. Chem. 279(41): 42860-42866.
• Huang W, Beharry Z, Zhang Z, Palzkill T. (2003). A broad-spectrum peptide inhibitor of beta-lactamase identified using phage display and peptide arrays. Protein Eng. 16(11): 853-860.
• Zhang Z, Palzkill T. (2003). Determinants of binding affinity and specificity for the interaction of TEM-1 and SME-1 beta-lactamase with beta -lactamase inhibitory protein. J. Biol. Chem. 278(46): 45706-45712.
• Zhang Z, Yu Y, Musser JM, Palzkill T. (2001). Amino acid sequence determinants of extended spectrum cephalosporin hydrolysis by the class C P99 beta-lactamase. J. Biol. Chem. 276(49): 46568-74.
• Huang W, Zhang Z, Palzkill T. (2000). Design of potent beta-lactamase inhibitors by phage display of beta-lactamase inhibitory protein. J. Biol. Chem. 275(20): 14964-8.
• Zhang Z, Qian M, Huang Q, Jia Y, Tang Y, Wang K, Cui D, Li M. (2001). Crystal structure of the complex of concanavalin A and hexapeptide. J. Protein Chem. 20(5): 423-9.
• Zhang Z, Qian M, Huang Q, Jia Y, Tang Y, Wang K, Cui D, Li M. (2001). Crystal structure of the complex of concanavalin A and tripeptide. J. Protein Chem. 20(1): 59-65.

Last edited on: January 03, 2006