title: Structural analysis of cytochrome P450 105N1 involved in the biosynthesis of the zincophore, coelibactin.
abstract: Coelibactin is a putative non-ribosomally synthesized peptide with predicted zincophore activity and which has been implicated in antibiotic regulation in Streptomyces coelicolor A3(2). The coelibactin biosynthetic pathway contains a stereo- and regio-specific monooxygenation step catalyzed by a cytochrome P450 enzyme (CYP105N1). We have determined the X-ray crystal structure of CYP105N1 at 2.9 Å and analyzed it in the context of the bacterial CYP105 family as a whole. The crystal structure reveals a channel between the α-helical domain and the β-sheet domain exposing the heme pocket and the long helix I to the solvent. This wide-open conformation of CYP105N1 may be related to the bulky substrate coelibactin. The ligand-free CYP105N1 structure has enough room in the substrate access channel to allow the coelibactin to enter into the active site. Analysis of typical siderophore ligands suggests that CYP105N1 may produce derivatives of coelibactin, which would then be able to chelate the zinc divalent cation.
authors.affiliation: Department of Biochemistry, School of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Institute of Life Science, Medical School, Swansea University, Singleton Park, Swansea, SA2 8PP, UK.
authors.forename: Suzy C
authors.initials: SC
authors.lastname: Moody
authors.affiliation: Institute of Pharmaceutical Science, King's College London, 5th Floor, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Hider
authors.affiliation: Department of Biochemistry, School of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Lei
authors.affiliation: Institute of Life Science, Medical School, Swansea University, Singleton Park, Swansea, SA2 8PP, UK.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kelly
authors.affiliation: Department of Biochemistry, School of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Waterman
authors.affiliation: Institute of Life Science, Medical School, Swansea University, Singleton Park, Swansea, SA2 8PP, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Lamb
mesh_terms: D001426:Bacterial Proteins / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics; D008958:Models, Molecular; D010080:Oxazoles / Q000378:metabolism*; D017433:Protein Structure, Secondary; D017262:Siderophores / Q000096:biosynthesis; D048372:Streptomyces coelicolor / Q000201:enzymology*; D013844:Thiazoles / Q000378:metabolism*; D015032:Zinc / Q000737:chemistry
chemical_list: D001426:Bacterial Proteins; D010080:Oxazoles; D017262:Siderophores; D013844:Thiazoles; C000600079:coelibactin; D003577:Cytochrome P-450 Enzyme System; D015032:Zinc