3N8Z

Crystal Structure of Cyclooxygenase-1 in Complex with Flurbiprofen

Summary for 3N8Z

• Entry DOI: 10.2210/pdb3n8z/pdb
• Related: 3N8V 3N8W 3N8X 3N8Y
• Descriptor: Prostaglandin G/H synthase 1, 2-acetamido-2-deoxy-alpha-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total)
• Functional Keywords: cox-1, cyclooxygenase, peroxidase, prostaglandin, heme, flurbiprofen, merohedral twinned, oxidoreductase
• Biological source: Ovis aries (sheep)
• Total number of polymer chains: 2
• Total formula weight: 133240.05

Authors

Sidhu, R.S. (deposition date: 2010-05-28, release date: 2010-07-28, Last modification date: 2024-11-06)

Primary citation

Sidhu, R.S.,Lee, J.Y.,Yuan, C.,Smith, W.L.
Comparison of Cyclooxygenase-1 Crystal Structures: Cross-Talk between Monomers Comprising Cyclooxygenase-1 Homodimers
Biochemistry, 49:7069-7079, 2010

PubMed Abstract: Prostaglandin endoperoxide H synthases (PGHSs)-1 and -2 (also called cyclooxygenases (COXs)-1 and -2) catalyze the committed step in prostaglandin biosynthesis. Both isoforms are targets of nonsteroidal antiinflammatory drugs (NSAIDs). PGHSs are homodimers that exhibit half-of-sites COX activity; moreover, some NSAIDs cause enzyme inhibition by binding only one monomer. To learn more about the cross-talk that must be occurring between the monomers comprising each PGHS-1 dimer, we analyzed structures of PGHS-1 crystallized under five different conditions including in the absence of any tightly binding ligand and in the presence of nonspecific NSAIDs and of a COX-2 inhibitor. When crystallized with substoichiometric amounts of an NSAID, both monomers are often fully occupied with inhibitor; thus, the enzyme prefers to crystallize in a fully occupied form. In comparing the five structures, we only observe changes in the positions of residues 123-129 and residues 510-515. In cases where one monomer is fully occupied with an NSAID and the partner monomer is incompletely occupied, an alternate conformation of the loop involving residues 123-129 is seen in the partially occupied monomer. We propose, on the basis of this observation and previous cross-linking studies, that cross-talk between monomers involves this mobile 123-129 loop, which is located at the dimer interface. In ovine PGHS-1 crystallized in the absence of an NSAID, there is an alternative route for substrate entry into the COX site different than the well-known route through the membrane binding domain.

PubMed: 20669977
DOI: 10.1021/bi1003298

Experimental method

X-RAY DIFFRACTION (2.9 Å)