Phospholipase A2 as a Target Protein for Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Crystal Structure of the Complex Formed between Phospholipase A2 and Oxyphenbutazone at 1.

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• 作者：Nagendra Singh ; Talat Jabeen ; Rishi K. Somvanshi ; Sujata Sharma ; Sharmistha Dey ; and Tej P. Singh
• 刊名：Biochemistry
• 出版年：2004
• 出版时间：November 23, 2004
• 年：2004
• 卷：43
• 期：46
• 页码：14577 - 14583
• 全文大小：429K
• 年卷期：v.43,no.46(November 23, 2004)
• ISSN：1520-4995

文摘

Phospholipase A₂ (PLA₂; EC 3.1.1.4) is a key enzyme involved in the production ofproinflammatory mediators known as eicosanoids. The binding of the substrate to PLA₂ occurs througha well-formed hydrophobic channel. To determine the viability of PLA₂ as a target molecule for thestructure-based drug design against inflammation, arthritis, and rheumatism, the crystal structure of thecomplex of PLA₂ with a known anti-inflammatory compound oxyphenbutazone (OPB), which has beendetermined at 1.6 Å resolution. The structure has been refined to an R factor of 0.209. The structurecontains 1 molecule each of PLA₂ and OPB with 2 sulfate ions and 111 water molecules. The bindingstudies using surface plasmon resonance show that OPB binds to PLA₂ with a dissociation constant of6.4 × 10^-8 M. The structure determination has revealed the presence of an OPB molecule at the bindingsite of PLA₂. It fits well in the binding region, thus displaying a high level of complementarity. Thestructure also indicates that OPB works as a competitive inhibitor. A large number of hydrophobicinteractions between the enzyme and the OPB molecule have been observed. The hydrophobic interactionsinvolving residues Tyr⁵² and Lys⁶⁹ with OPB are particularly noteworthy. Other residues of the hydrophobicchannel such as Leu³, Phe⁵, Met⁸, Ile⁹, and Ala¹⁸ are also interacting extensively with the inhibitor. Thecrystal structure clearly reveals that the binding of OPB to PLA₂ is specific in nature and possibly suggeststhat the basis of its anti-inflammatory effects may be due to its binding to PLA₂ as well.