PDBsum entry 1q4g

Oxidoreductase

PDB id: 1q4g

Contents

Protein chains

553 a.a. *

Ligands

NAG-NDG ×2

NAG-NAG-BMA-BMA ×2

NAG-NDG-BMA-MAN-MAN

NAG-NDG-BMA-BMA-BMA

BOG ×8

BFL ×2

HEM ×2

GOL ×5

Waters ×654

* Residue conservation analysis

References listed in PDB file

Key reference

Title

The 2.0 a resolution crystal structure of prostaglandin h2 synthase-1: structural insights into an unusual peroxidase.

Authors

K.Gupta, B.S.Selinsky, C.J.Kaub, A.K.Katz, P.J.Loll.

Ref.

J Mol Biol, 2004, 335, 503-518. [DOI no: 10.1016/j.jmb.2003.10.073]

PubMed id

14672659

Abstract

Prostaglandin H2 synthase (EC 1.14.99.1) is an integral membrane enzyme containing a cyclooxygenase site, which is the target for the non-steroidal anti-inflammatory drugs, and a spatially distinct peroxidase site. Previous crystallographic studies of this clinically important drug target have been hindered by low resolution. We present here the 2.0 A resolution X-ray crystal structure of ovine prostaglandin H2 synthase-1 in complex with alpha-methyl-4-biphenylacetic acid, a defluorinated analog of the non-steroidal anti-inflammatory drug flurbiprofen. Detergent molecules are seen to bind to the protein's membrane-binding domain, and their positions suggest the depth to which this domain is likely to penetrate into the lipid bilayer. The relation of the enzyme's proximal heme ligand His388 to the heme iron is atypical for a peroxidase; the iron-histidine bond is unusually long and a substantial tilt angle is observed between the heme and imidazole planes. A molecule of glycerol, used as a cryoprotectant during diffraction experiments, is seen to bind in the peroxidase site, offering the first view of any ligand in this active site. Insights gained from glycerol binding may prove useful in the design of a peroxidase-specific ligand.

Figure 3.
Figure 3. Stereoscopic diagram of the PGHS monomer. The structural domains are colored as follows: the EGF-like domain, green; the membrane-binding domain, yellow; and the catalytic domain, blue. The cyclooxygenase inhibitor a-methyl-4-biphenylacetic acid is depicted as an orange space-filling model, and glycerol molecules are depicted as pink space-filling models. PGHS features three sites of glycosylation, Asn68, Asn144, and Asn410. The carbohydrate molecules are shown in yellow ball-and-stick representations. Several molecules of the non-ionic detergent b-OG (black and red ball-and-stick) used in the crystallization of PGHS are bound near the membrane-binding domain. This Figure was prepared using MOLSCRIPT.[85.]

Figure 9.
Figure 9. (a) Stereoscopic view of the peroxidase active site of PGHS-1. Glycerol is rendered as a ball-and-stick model. Small individual spheres represent water molecules, while the large sphere at the center of the porphyrin represents the iron atom. This Figure was prepared using MOLSCRIPT.[85.] (b) Simulated annealing omit map density for glycerol bound within the peroxidase active site of PGHS (F[o] -F[c] map contoured at 4.0 s). The view is from above the peroxidase active site, looking down onto the heme. The porphyrin can be seen in the background of the Figure. This panel was prepared using PYMOL (http://www.pymol.org).

The above figures are reprinted by permission from Elsevier: J Mol Biol (2004, 335, 503-518) copyright 2004.