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J. Biol. Chem., Vol. 280, Issue 13, 12405-12412, April 1, 2005

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Crystal Structure of the Cysteine-rich Secretory Protein Stecrisp Reveals That the Cysteine-rich Domain Has a K⁺ Channel Inhibitor-like Fold^*

Min Guo, Maikun Teng, Liwen Niu, Qun Liu¶, Qingqiu Huang¶, and Quan Hao¶

From the Key Laboratory of Structural Biology, Chinese Academy of Sciences, Department of Molecular and Cell Biology, School of Life Sciences, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026, China and the ^¶Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853

Stecrisp from Trimeresurus stejnegeri snake venom belongs to a family of cysteine-rich secretory proteins (CRISP) that have various functions related to sperm-egg fusion, innate host defense, and the blockage of ion channels. Here we present the crystal structure of stecrisp refined to 1.6-Å resolution. It shows that stecrisp contains three regions, namely a PR-1 (pathogenesis-related proteins of group1) domain, a hinge, and a cysteine-rich domain (CRD). A conformation of solvent-exposed and -conserved residues (His⁶⁰, Glu⁷⁵, Glu⁹⁶, and His¹¹⁵) in the PR-1 domain similar to that of their counterparts in homologous structures suggests they may share some molecular mechanism. Three flexible loops of hypervariable sequence surrounding the possible substrate binding site in the PR-1 domain show an evident difference in homologous structures, implying that a great diversity of species- and substrate-specific interactions may be involved in recognition and catalysis. The hinge is fixed by two crossed disulfide bonds formed by four of ten characteristic cysteines in the carboxyl-terminal region and is important for stabilizing the N-terminal PR-1 domain. Spatially separated from the PR-1 domain, CRD possesses a similar fold with two K⁺ channel inhibitors (Bgk and Shk). Several candidates for the possible functional sites of ion channel blocking are located in a solvent-exposed loop in the CRD. The structure of stecrisp will provide a prototypic architecture for a structural and functional exploration of the diverse members of the CRISP family.

Received for publication, December 2, 2004 , and in revised form, December 10, 2004.

^* This project was supported by Chinese National Natural Science Foundation Grants 30121001, 39830080, 30025012, and 30130080, Chinese Ministry of Science and Technology Grants G1999075603 and 2002BA711A13 (the "973" and "863" plans), and Chinese Academy of Sciences Grants KSCX1-SW-17, STZ98-2-12, and STZ01-29 (to L. N. and M. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The atomic coordinates and structure factors (code 1RC9) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

To whom correspondence should be addressed. Tel.: 86-551-3606334; Fax: 86-551-3603046; E-mail: lwniu{at}ustc.edu.cn.

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