The crystal structure of human group X (hGX) secreted phospholipase A 2 (sPLA 2 ) has been solved to a resolution of 1.97 Å. As expected the protein fold is similar to previously reported sPLA 2 structures. The active site architecture, including the positions of the catalytic residues and the first and second shell water around the Ca 2؉ cofactor, are highly conserved and remarkably similar to the group IB and group IIA enzymes. Differences are seen in the structures following the

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... nal helix and at the C terminus. These regions are proposed to interact with the substrate membrane surface. The opening to the active site slot is considerably larger in hGX than in human group IIA sPLA 2 . Furthermore, the electrostatic surface potential of the hGX interfacial-binding surface does not resemble that of the human group IIA sPLA 2 ; the former is highly neutral, whereas the latter is highly cationic. The cationic residues on this face of group IB and IIA enzymes have been implicated in membrane binding and in k cat * allostery. In contrast, hGX does not show activation by the anionic charge at the lipid interface when acting on phospholipid vesicles or short-chain phospholipid micelles. Together, the crystal structure and kinetic results of hGX supports the conclusion that it is as active on zwitterionic as on anionic interfaces, and thus it is predicted to target the zwitterionic membrane surfaces of mammalian cells. Recent molecular cloning studies have shown that mammals contain a large number of secreted phospholipases A 2 (sPLA 2 ), 1 9 gene products in humans and 10 in mice (1, 2). These 14 -18-