title: Chemical and structural diversity in cyclooxygenase protein active sites.
abstract: A major pharmaceutical problem is designing diverse and selective lead compounds. The human genome sequence provides opportunities to discover compounds that are protein selective if we can develop methods to identify specificity determinants from sequence alone. We have analyzed sequence and structural diversity of sheep COX-1 and mouse COX-2 proteins by Active Site Profiling (ASP). Eleven residues that should serve as specificity determinants between COX-1 and COX-2 were identified; however, the literature suggests that only one has been utilized in structure-based discovery. ASP was used to create a position-specific scoring matrix, which was used to identify possible cross-reacting proteins from the human sequences. This method proved selective for cyclooxygenases, comparing well with results using BLAST. The methods identify a probable misannotation of a cyclooxygenase in which there is high sequence similarity scores using BLAST, but ASP shows it does not contain the residues necessary for cyclooxygenase function. ASP Analysis of human COX proteins suggests that some specificity determinants that distinguish COX-1 and COX-2 proteins are similar between sheep COX-1/mouse COX-2 and human COX-1/COX2; however, residue identities at those positions are not necessarily conserved. Our results lay groundwork for development of family-specific pattern recognition methods to selectively match compounds with proteins.
authors.affiliation: Department of Computer Science, Wake Forest University, Winston-Salem, NC, USA.
authors.forename: Ryan G
authors.initials: RG
authors.lastname: Huff
authors.forename: Ersin
authors.initials: E
authors.lastname: Bayram
authors.forename: Huan
authors.initials: H
authors.lastname: Tan
authors.forename: Stacy T
authors.initials: ST
authors.lastname: Knutson
authors.forename: Michael H
authors.initials: MH
authors.lastname: Knaggs
authors.forename: Allen B
authors.initials: AB
authors.lastname: Richon
authors.forename: Peter
authors.initials: P
authors.lastname: Santago
authors.forename: Jacquelyn S
authors.initials: JS
authors.lastname: Fetrow
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D051545:Cyclooxygenase 1 / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D034561:Sheep, Domestic
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human