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PDBsum entry 1pgf
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Oxidoreductase
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PDB id
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1pgf
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Synthesis and use of iodinated nonsteroidal antiinflammatory drug analogs as crystallographic probes of the prostaglandin h2 synthase cyclooxygenase active site.
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Authors
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P.J.Loll,
D.Picot,
O.Ekabo,
R.M.Garavito.
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Ref.
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Biochemistry, 1996,
35,
7330-7340.
[DOI no: ]
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PubMed id
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Abstract
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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.
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Secondary reference #1
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Title
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The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin h2 synthase.
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Authors
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P.J.Loll,
D.Picot,
R.M.Garavito.
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Ref.
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Nat Struct Biol, 1995,
2,
637-643.
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PubMed id
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Secondary reference #2
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Title
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The X-Ray crystal structure of the membrane protein prostaglandin h2 synthase-1.
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Authors
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D.Picot,
P.J.Loll,
R.M.Garavito.
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Ref.
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Nature, 1994,
367,
243-249.
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PubMed id
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