1pgf
From Proteopedia
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PROSTAGLANDIN H2 SYNTHASE-1 COMPLEXED WITH 1-(4-IODOBENZOYL)-5-METHOXY-2-METHYLINDOLE-3-ACETIC ACID (IODOINDOMETHACIN), CIS MODEL
Overview
The cyclooxygenase activity of the membrane protein prostaglandin H2, synthase isoform 1 (PGHS-1) is the target of the nonsteroidal, antiinflammatory drugs (NSAIDs). The X-ray crystal structures of PGHS-1 in, complex with the NSAIDs flurbiprofen and bromoaspirin have been determined, previously [Picot, D., et al. (1994) Nature 367, 243-249; Loll, P. J., et, al. (1995) Nat. Struct. Biol. 2, 637-643]. We report here the preparation, and characterization of novel potent iodinated analogs of the NSAIDs, indomethacin and suprofen, as well as the refined X-ray crystal structures, of their complexes with PGHS-1. The PGHS-iodosuprofen complex structure, has been refined at 3.5 A to an R-value of 0.189 and shows the suprofen, analog to share a common mode of binding with flurbiprofen. The, PGHS-iodoindomethacin complex structure has been refined at 4.5 A to an, R-value of 0.254. The low resolution of the iodoindomethacin complex, structure precludes detailed modeling of drug-enzyme interactions, but the, electron-dense iodine atom of the inhibitor has been unambiguously, located, allowing for the placement and approximate orientation of the, inhibitor in the enzyme's active site. We have modeled two equally likely, binding modes for iodoindomethacin, corresponding to the two principal, conformers of the inhibitor. Like flurbiprofen, iodosuprofen and, iodoindomethacin bind at the end of the long channel which leads into the, enzyme active site. Binding at this site presumably blocks access of, substrate to Tyr-385, a residue essential for catalysis. No evidence is, seen for significant protein conformational differences between the, iodoindomethacin and iodosuprofen of flurbiprofen complex structures.
About this Structure
1PGF is a Single protein structure of sequence from Ovis aries with , and as ligands. Active as Prostaglandin-endoperoxide synthase, with EC number 1.14.99.1 Known structural/functional Sites: , , and . Full crystallographic information is available from OCA.
Reference
Synthesis and use of iodinated nonsteroidal antiinflammatory drug analogs as crystallographic probes of the prostaglandin H2 synthase cyclooxygenase active site., Loll PJ, Picot D, Ekabo O, Garavito RM, Biochemistry. 1996 Jun 11;35(23):7330-40. PMID:8652509
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