title: Molecular basis for triclosan activity involves a flipping loop in the active site.
abstract: The crystal structure of the Escherichia coli enoyl reductase-NAD+-triclosan complex has been determined at 2.5 A resolution. The Ile192-Ser198 loop is either disordered or in an open conformation in the previously reported structures of the enzyme. This loop adopts a closed conformation in our structure, forming van der Waals interactions with the inhibitor and hydrogen bonds with the bound NAD+ cofactor. The opening and closing of this flipping loop is likely an important factor in substrate or ligand recognition. The closed conformation of the loop appears to be a critical feature for the enhanced binding potency of triclosan, and a key component in future structure-based inhibitor design.
authors.affiliation: Department of Structural Biology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA. xiayang_qiu-1@sbphrd.com
authors.forename: X
authors.initials: X
authors.lastname: Qiu
authors.forename: C A
authors.initials: CA
authors.lastname: Janson
authors.forename: R I
authors.initials: RI
authors.lastname: Court
authors.forename: M G
authors.initials: MG
authors.lastname: Smyth
authors.forename: D J
authors.initials: DJ
authors.lastname: Payne
authors.forename: S S
authors.initials: SS
authors.lastname: Abdel-Meguid
mesh_terms: D000595:Amino Acid Sequence; D000891:Anti-Infective Agents, Local / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); D004926:Escherichia coli / Q000201:enzymology; D006860:Hydrogen Bonding; D007532:Isoleucine; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009243:NAD / Q000737:chemistry / Q000378:metabolism*; D010088:Oxidoreductases / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D012694:Serine; D014260:Triclosan / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000891:Anti-Infective Agents, Local; D007532:Isoleucine; D009243:NAD; D012694:Serine; D014260:Triclosan; D010088:Oxidoreductases; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)