5KIR

The Structure of Vioxx Bound to Human COX-2

Summary for 5KIR

• Entry DOI: 10.2210/pdb5kir/pdb
• Descriptor: Prostaglandin G/H synthase 2, alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, Rofecoxib, ... (9 entities in total)
• Functional Keywords: cyclooxyrgenase, vioxx, rofecoxib, cox, oxidoreductase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 131003.98

Authors

Orlando, B.J.,Malkowski, M.G. (deposition date: 2016-06-16, release date: 2016-09-28, Last modification date: 2024-11-13)

Primary citation

Orlando, B.J.,Malkowski, M.G.
Crystal structure of rofecoxib bound to human cyclooxygenase-2.
Acta Crystallogr.,Sect.F, 72:772-776, 2016

PubMed Abstract: Rofecoxib (Vioxx) was one of the first selective cyclooxygenase-2 (COX-2) inhibitors (coxibs) to be approved for use in humans. Within five years after its release to the public, Vioxx was withdrawn from the market owing to the adverse cardiovascular effects of the drug. Despite the widespread knowledge of the development and withdrawal of Vioxx, relatively little is known at the molecular level about how the inhibitor binds to COX-2. Vioxx is unique in that the inhibitor contains a methyl sulfone moiety in place of the sulfonamide moiety found in other coxibs such as celecoxib and valdecoxib. Here, new crystallization conditions were identified that allowed the structural determination of human COX-2 in complex with Vioxx and the structure was subsequently determined to 2.7 Å resolution. The crystal structure provides the first atomic level details of the binding of Vioxx to COX-2. As anticipated, Vioxx binds with its methyl sulfone moiety located in the side pocket of the cyclooxygenase channel, providing support for the isoform selectivity of this drug.

PubMed: 27710942
DOI: 10.1107/S2053230X16014230

Experimental method

X-RAY DIFFRACTION (2.697 Å)