doi: 10.1016/s0092-8674(00)80744-8.
Crystal structure of human cytosolic phospholipase A2 reveals a novel topology and catalytic mechanism
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- PMID: 10319815
- DOI: 10.1016/s0092-8674(00)80744-8
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Crystal structure of human cytosolic phospholipase A2 reveals a novel topology and catalytic mechanism
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Abstract
Cytosolic phospholipase A2 initiates the biosynthesis of prostaglandins, leukotrienes, and platelet-activating factor (PAF), mediators of the pathophysiology of asthma and arthritis. Here, we report the X-ray crystal structure of human cPLA2 at 2.5 A. cPLA2 consists of an N-terminal calcium-dependent lipid-binding/C2 domain and a catalytic unit whose topology is distinct from that of other lipases. An unusual Ser-Asp dyad located in a deep cleft at the center of a predominantly hydrophobic funnel selectively cleaves arachidonyl phospholipids. The structure reveals a flexible lid that must move to allow substrate access to the active site, thus explaining the interfacial activation of this important lipase.
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