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J. Biol. Chem., Vol. 280, Issue 8, 7326-7335, February 25, 2005

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A Molecular Mechanism for Lys⁴⁹-Phospholipase A₂ Activity Based on Ligand-induced Conformational Change^*

Andre L. B. Ambrosio, M. Cristina Nonato, Heloísa S. Selistre de Araújo¶, Raghuvir Arni||, Richard J. Ward**, Charlotte L. Ownby, Dulce H. F. de Souza, and Richard C. Garratt

From the Centro de Biotecnologia Molecular Estrutural, Instituto de Física de São Carlos, USP, São Carlos-SP CEP 13560-970, Brazil, the Departamento de Fïsica e Quïmica, FCFRP/USP, Ribeirão Preto-SP CEP 14040-901, Brazil, ^¶Centro de Biotecnologia Molecular Estrutural, the Departamento de Ciências Fisiológicas, UFSCar, São Carlos-SP CEP 13565-905, Brazil, the ^||Departamento de Fïsica, IBILCE/UNESP, São José do Rio Preto-SP CEP 15054-000, Brazil, the ^**Departamento de Quïmica, FFCLRP/USP, Ribeirão Preto-SP CEP 14040-901, Brazil, and the Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma 74078

Agkistrodon contortrix laticinctus myotoxin is a Lys⁴⁹-phospholipase A₂ (EC 3.1.1.4) isolated from the venom of the serpent A. contortrix laticinctus (broad-banded copperhead). We present here three monomeric crystal structures of the myotoxin, obtained under different crystallization conditions. The three forms present notable structural differences and reveal that the presence of a ligand in the active site (naturally presumed to be a fatty acid) induces the exposure of a hydrophobic surface (the hydrophobic knuckle) toward the C terminus. The knuckle in A. contortrix laticinctus myotoxin involves the side chains of Phe¹²¹ and Phe¹²⁴ and is a consequence of the formation of a canonical structure for the main chain within the region of residues 118–125. Comparison with other Lys⁴⁹-phospholipase A₂ myotoxins shows that although the knuckle is a generic structural motif common to all members of the family, it is not readily recognizable by simple sequence analyses. An activation mechanism is proposed that relates fatty acid retention at the active site to conformational changes within the C-terminal region, a part of the molecule that has long been associated with Ca²⁺-independent membrane damaging activity and myotoxicity. This provides, for the first time, a direct structural connection between the phospholipase "active site" and the C-terminal "myotoxic site," justifying the otherwise enigmatic conservation of the residues of the former in supposedly catalytically inactive molecules.

Received for publication, September 14, 2004 , and in revised form, December 6, 2004.

The atomic coordinates and structure factors (codes 1S8g (form I), 1S8H (form II), and 1S8I (form III)) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo Process Grant 00/14959-8, FAPESP/CEPID, and CNPq/PRONEX. 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.

To whom correspondence should be addressed: Caixa Postal 369, CEP 13560-970, São Carlos-SP, Brazil. Tel.: 55-16-3373-9881; Fax: 55-16-3373-9881; E-mail: richard{at}if.sc.usp.br.

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