1JQ8

Design of specific inhibitors of phospholipase A2: Crystal structure of a complex formed between phospholipase A2 from Daboia russelli pulchella and a designed pentapeptide Leu-Ala-Ile-Tyr-Ser at 2.0 resolution

Summary for 1JQ8

• Entry DOI: 10.2210/pdb1jq8/pdb
• Related: 1CL5 1FB2 1FE7 1FV0 1JQ9
• Descriptor: Phospholipase A2, Peptide inhibitor, SULFATE ION, ... (5 entities in total)
• Functional Keywords: neurotoxic, designed peptide, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Daboia russellii pulchella; More
• Total number of polymer chains: 3
• Total formula weight: 28101.41

Authors

Chandra, V.,Jasti, J.,Kaur, P.,Dey, S.,Betzel, C.,Singh, T.P. (deposition date: 2001-08-04, release date: 2002-11-06, Last modification date: 2024-11-20)

Primary citation

Chandra, V.,Jasti, J.,Kaur, P.,Dey, S.,Srinivasan, A.,Betzel, C.h.,Singh, T.P.
Design of specific peptide inhibitors of phospholipase A2: structure of a complex formed between Russell's viper phospholipase A2 and a designed peptide Leu-Ala-Ile-Tyr-Ser (LAIYS).
ACTA CRYSTALLOGR.,SECT.D, 58:1813-1819, 2002

PubMed Abstract: Phospholipase A(2) (EC 3.1.1.4) is a key enzyme of the cascade mechanism involved in the production of proinflammatory compounds known as eicosanoids. The binding of phospholipase A(2) to membrane surfaces and the hydrolysis of phospholipids are thought to involve the formation of a hydrophobic channel into which a single substrate molecule diffuses before cleavage. In order to regulate the production of proinflammatory compounds, a specific peptide inhibitor of PLA(2), Leu-Ala-Ile-Tyr-Ser, has been designed. Phospholipase A(2) from Daboia russelli pulchella (DPLA(2)) and peptide Leu-Ala-Ile-Tyr-Ser (LAIYS) have been co-crystallized. The structure of the complex has been determined and refined to 2.0 A resolution. The structure contains two crystallographically independent molecules of DPLA(2), with one molecule of peptide specifically bound to one of them. The overall conformations of the two molecules are essentially similar except in three regions; namely, the calcium-binding loop including Trp31 (residues 25-34), the beta-wing consisting of two antiparallel beta-strands (residues 74-85) and the C-terminal region (residues 119-133). Of these, the most striking difference pertains to the orientation of Trp31 in the two molecules. The conformation of Trp31 in molecule A was suitable to allow the binding of peptide LAIYS, while that in molecule B prevented the entry of the ligand into the hydrophobic channel. The structure of the complex clearly showed that the OH group of Tyr of the inhibitor formed hydrogen bonds with both His48 N(delta1) and Asp49 O(delta1), while O(gamma)H of Ser was involved in a hydrogen bond with Trp31. Other peptide backbone atoms interact with protein through water molecules, while Leu, Ala and Ile form strong hydrophobic interactions with the residues of the hydrophobic channel.

PubMed: 12351825
DOI: 10.1107/S0907444902013720

Experimental method

X-RAY DIFFRACTION (2 Å)