1mf4
From Proteopedia
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Structure-based design of potent and selective inhibitors of phospholipase A2: Crystal structure of the complex formed between phosholipase A2 from Naja Naja sagittifera and a designed peptide inhibitor at 1.9 A resolution
Overview
Phospholipase A(2) (PLA(2)) (E. C. 3.1.1.4) is a common enzyme in the, two-way cascade mechanism leading to the production of proinflammatory, compounds known as eicosanoids. The binding of phospholipase A(2) to the, membrane surface and hydrolysis of phospholipids are thought to involve, the formation of a hydrophobic channel into which a single substrate, molecule diffuses before its cleavage. To regulate the production of, proinflammatory compounds, a specific peptide inhibitor, Val-Ala-Phe-Arg-Ser (VAFRS) for the group I PLA(2) enzymes has been, designed and synthesized. PLA(2) was isolated from Indian cobra (Naja naja, sagittifera) venom and purified to homogeneity. The binding studies, indicated the K(i) value of 1.02 +/- 0.10 x 10(-8) M. The purified PLA(2), samples and the designed inhibitor VAFRS were cocrystallized. The crystal, structure of the complex was determined and refined to 1.9 A resolution., The peptide binds to PLA(2) at the active site and fills the hydrophobic, channel completely. However, its placement with respect to the channel is, in the opposite direction as compared to those observed in group II, PLA(2)'s. Furthermore, the predominant intermolecular interactions involve, strong electrostatic interactions between the side chains of peptide Arg, and Asp 49 of PLA(2) together with a number of van der Waals interactions, with other residues. A good number of observed interactions between the, peptide and the protein indicate the significance of a structure-based, drug design approach. The novel factor in the present sequence of the, peptide is related to the introduction of a positively charged residue at, the C-terminal part of the peptide.
About this Structure
1MF4 is a Single protein structure of sequence from Naja sagittifera with CA as ligand. Active as Phospholipase A(2), with EC number 3.1.1.4 Full crystallographic information is available from OCA.
Reference
Design of specific peptide inhibitors for group I phospholipase A2: structure of a complex formed between phospholipase A2 from Naja naja sagittifera (group I) and a designed peptide inhibitor Val-Ala-Phe-Arg-Ser (VAFRS) at 1.9 A resolution reveals unique features., Singh RK, Vikram P, Makker J, Jabeen T, Sharma S, Dey S, Kaur P, Srinivasan A, Singh TP, Biochemistry. 2003 Oct 14;42(40):11701-6. PMID:14529280
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