PDBsum entry 1pgf

Oxidoreductase

PDB id: 1pgf

Contents

Protein chains

551 a.a. *

Ligands

NAG-NAG ×2

NAG ×4

HEM ×2

IMM ×2

* Residue conservation analysis

PDB id:

1pgf

Name:

Oxidoreductase

Title:

Prostaglandin h2 synthase-1 complexed with 1-(4-iodobenzoyl)-5- methoxy-2-methylindole-3-acetic acid (iodoindomethacin), cis model

Structure:

Prostaglandin h2 synthase-1. Chain: a, b. Synonym: cyclooxygenase i. Ec: 1.14.99.1

Source:

Ovis aries. Sheep. Organism_taxid: 9940. Organelle: seminal vesicle

Biol. unit:

Dimer (from PQS)

Resolution:

4.50Å R-factor: 0.254 R-free: 0.267

Authors:

P.J.Loll,D.Picot,R.M.Garavito

Key ref:

P.J.Loll et al. (1996). Synthesis and use of iodinated nonsteroidal antiinflammatory drug analogs as crystallographic probes of the prostaglandin H2 synthase cyclooxygenase active site. Biochemistry, 35, 7330-7340. PubMed id: 8652509 DOI: 10.1021/bi952776w

Date:

02-Dec-95 Release date: 11-Jan-97

Protein chains

P05979  (PGH1_SHEEP) -  Prostaglandin G/H synthase 1 from Ovis aries

Seq: 600 a.a.

Struc: 551 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.1.14.99.1 - prostaglandin-endoperoxide synthase.
• Reaction: (5Z,8Z,11Z,14Z)-eicosatetraenoate + AH2 + 2 O2 = prostaglandin H2 + A + H2O

(5Z,8Z,11Z,14Z)-eicosatetraenoate + AH2 + 2 × O2 = prostaglandin H2 + + H2O (Bound ligand (Het Group name = HEM) matches with 51.11% similarity)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1021/bi952776w

Biochemistry 35:7330-7340 (1996)

PubMed id: 8652509

Synthesis and use of iodinated nonsteroidal antiinflammatory drug analogs as crystallographic probes of the prostaglandin H2 synthase cyclooxygenase active site.

P.J.Loll, D.Picot, O.Ekabo, R.M.Garavito.

ABSTRACT

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.