Crystal structure of human cytosolic phospholipase A2 reveals a novel topology and catalytic mechanism

Cell. 1999 Apr 30;97(3):349-60. doi: 10.1016/s0092-8674(00)80744-8.


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.

MeSH terms

  • Animals
  • Arachidonic Acid / metabolism
  • Binding Sites / genetics*
  • CHO Cells
  • Calcium / metabolism*
  • Catalytic Domain / genetics*
  • Cricetinae
  • Crystallography, X-Ray
  • Cytosol / enzymology
  • Humans
  • Hydrolases / chemistry
  • Hydrolases / metabolism
  • Molecular Sequence Data
  • Phospholipases A / chemistry*
  • Phospholipases A / genetics
  • Phospholipases A / metabolism*
  • Phospholipases A2
  • Phospholipids / metabolism
  • Protein Folding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Sequence Homology, Amino Acid
  • Solvents


  • Phospholipids
  • Solvents
  • Arachidonic Acid
  • Hydrolases
  • Phospholipases A
  • Phospholipases A2
  • Calcium

Associated data

  • PDB/1CJY