Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 335, Issue 2, Pages 503-518Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2003.10.073
Keywords
cyclooxygenase; non-steroidal anti-inflammatory drug; peroxidase; prostaglandin synthase; membrane binding domain
Categories
Funding
- NIGMS NIH HHS [GM55171] Funding Source: Medline
Ask authors/readers for more resources
Prostaglandin H-2 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 Angstrom resolution X-ray crystal structure of ovine prostaglandin H-2 synthase-1 in complex with alpha-methyl-4-biphenylacetic-methyl-4-biphenylacetic acid, a defluorinated analog of the non- steroidal anti-inflammatory drug flurbiprofen. Detergent molecules are seen to bind to the proteins 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. (C) 2003 Elsevier Ltd. All rights reserved.
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