department of pharmacology

Vivien Yee, Ph.D

Yee

Associate Professor

School of Medicine
Case Western Reserve University

Department of Biochemistry

10900 Euclid Avenue
Cleveland, Ohio 44106

Phone: (216) 368-1184
Fax: (216) 368-3419
E-mail: vivien.yee@case.edu

Research

Detailed three-dimensional molecular models determined by single-crystal X-ray diffraction methods provide a wealth of information, bringing insight into protein structure-function relationships, guiding protein engineering studies, and aiding the computational design of small-molecule inhibitors. Our laboratory combines crystallography with modeling and mutagenesis studies to study several systems. The first of these focus on serine proteases which are central in blood coagulation. We are interested in enzyme:substrate peptide structures, to provide some insight into the effect of clinically relevant polymorphisms and into substrate recognition. We are also studying the prion protein, which is implicated in an intriguing family of neurological diseases, the spongiform encephalopathies. Prion protein structures may be helpful in understanding the structural transformation of the protein that is believed to be a key event in the disease. A third project is provided by the 2'-5'-oligoadenylate synthetase enzyme, which is part of an interferon-induced, mammalian antiviral defense system. We are pursuing structures to gain some insight into the mechanism of dsRNA-activation and the determinants of the enzyme's 2'-specificity. Finally, we are investigating the 1.2 million Dalton transcarboxylase multienzyme complex. Our structures of its large 5S and 12S catalytic subunits serve as models for related mammalian metabolic enzymes, and allow us to speculate on mechanisms and the structural consequences of disease mutations.

SELECTED REFERENCES:

R. Hartmann, J. Justesen, S.N. Sarkar, G.C. Sen, and V.C. Yee. Structural basis for 2’-specificity and double-stranded RNA activation of the interferon-induced antiviral protein 2’-5’-oligoadenylate synthetase. Mol. Cell, 12, 1173-1185 (2003).

P.R. Hall, Y.-F. Wang, R.E. Rivera-Hainaj, X. Zheng, M. Pustai-Carey, P.R. Carey, and V.C. Yee. Transcarboxylase 12S crystal structure: hexamer assembly and substrate binding to a multienzyme core. EMBO J., 22, 2334-2347 (2003).

V.K. Lishko, B. Kudryk, V.P. Yakubenko, V.C. Yee, and T.P. Ugarova. Regulated unmasking of the cryptic binding site for integrin aMb2 in the gC-domain of fibrinogen. Biochemistry 41,12942-12951 (2002).

K.J. Knaus, M. Morillas, W. Swietnicki, M. Malone, W.K. Surewicz, and V.C. Yee. Crystal structure of the human prion protein reveals a mechanism for oligomerization. Nature Struct. Biol. 8, 770-774 (2001).

C. Sadasivan and V.C. Yee. Interaction of the factor XIII activation peptide with a-thrombin: crystal structure of its enzyme-substrate analog complex. J. Biol. Chem., 47, 36942-36948 (2000)

F. van den Akker, X. Zhang, M. Miyagi, X. Huo, K.S. Misono, and V.C. Yee. Structure of the dimerized hormone binding domain of a guanylyl cyclase-coupled receptor. Nature 406, 101-104 (2000).