Journal
JOURNAL OF MOLECULAR RECOGNITION
Volume 22, Issue 6, Pages 437-445Publisher
WILEY
DOI: 10.1002/jmr.960
Keywords
PLA(2); anti-inflammatory; anti-coagulant; indomethacin; crystal structure; enzyme
Categories
Funding
- Department of Biotechnology (DBT)
- Ministry of Science and Technology, New Delhi
- Department of Science and Technology (DST)
- Council of Scientific and Industrial Research (CSIR), New Delhi
- University Grants Commission (UGC), New Delhi
Ask authors/readers for more resources
A novel ligand-binding site with functional implications has been identified in phospholipase A(2) (PLA(2)). The binding of non-steroidal anti-inflammatory agent indomethacin at this site blocks both catalytic and anti-coagulant actions of PLA(2). A group IIIA PLA(2) has been isolated from Daboia russelli putchella (Russell's viper) which is enzymatically active as well as induces a strong anti-coagulant action. The binding studies have shown that indomethacin reduces the effects of both anti-coagulant and pro-inflammatory actions of PLA(2). group IIIA PLA(2) was co-crystallized with indomethacin and the structure of the complex has been determined at 1.4 angstrom resolution. The structure determination has revealed the presence of an indomethacin molecule in the structure of PLA(2) at a site which is distinct from the conventional substrate-binding site. One of the carboxylic group oxygen atoms of indomethacin interacts with Asp 49 and His 48 through the catalytically important water molecule OW 18 while the second carboxylic oxygen atom forms an ionic interaction with the side chain of Lys 69. It is well known that the residues, His 48 and Asp 49 are essential for catalysis while Lys 69 is a part of the anti-coagulant loop (residues, 54-77). Indomethacin binds in such a manner that it blocks the access to both, it works as a dual inhibitor for catalytic and anti-coagulant actions of PLA(2). This new binding site in PLA(2) has been observed for the first time and indomethacin is the first compound that has been shown to bind at this novel site resulting in the prevention of anti-coagulation and inflammation. Copyright (C) 2009 John Wiley & Sons, Ltd.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available