title: Conformational Analysis of an Antibacterial Cyclodepsipeptide Active against Mycobacterium tuberculosis by a Combined ROE and RDC Analysis.
abstract: Griselimycin (GM) and methylgriselimycin (MGM), naturally produced by microorganisms of the genus Streptomyces, are cyclic depsipeptides composed of ten amino acids. They exhibit antibacterial activity against Mycobacterium species by inhibiting the sliding clamp of prokaryotic DNA polymerase III and are therefore considered as potential anti-tuberculosis drugs. The difference between the peptides is the presence of l-(R)-4-methyl-proline in MGM instead of l-proline in GM at position 8 of the amino acid sequence. Methylation increases both metabolic stability and activity of MGM compared to GM. To get deeper insight into the structure-activity relationship, the solution structure of the cyclic part of MGM was determined using rotating-frame nuclear Overhauser effect (ROE) distance restraints and residual dipolar couplings (RDC). The structure of MGM in solution is compared to the structure of GM in a co-crystal with DNA polymerase III subunit beta. As a result, a highly defined structural model of MGM is obtained, which shows related characteristics to the bound GM.
authors.affiliation: Sanofi-Aventis GmbH, Department of Chemistry, Industriepark Hoechst, 65926, Frankfurt am Main, Germany.|Technische Universität Darmstadt, Clemens-Schöpf-Institut für Organische Chemie und Biochemie, Alarich-Weiss-Straße 4, 64287, Darmstadt, Germany.
authors.forename: Maic
authors.initials: M
authors.lastname: Fredersdorf
authors.affiliation: Sanofi-Aventis GmbH, Department of Chemistry, Industriepark Hoechst, 65926, Frankfurt am Main, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kurz
authors.affiliation: Sanofi-Aventis GmbH, Department of Chemistry, Industriepark Hoechst, 65926, Frankfurt am Main, Germany.
authors.forename: Armin
authors.initials: A
authors.lastname: Bauer
authors.affiliation: ETH Zürich, Laboratorium für Organische Chemie, D-CHAB, Vladimir-Prelog-Weg 3, 8093, Zürich, Switzerland.
authors.forename: Marc-Olivier
authors.initials: MO
authors.lastname: Ebert
authors.affiliation: ETH Zürich, Laboratorium für Organische Chemie, D-CHAB, Vladimir-Prelog-Weg 3, 8093, Zürich, Switzerland.
authors.forename: Carla
authors.initials: C
authors.lastname: Rigling
authors.affiliation: Present address: Center for Biomolecular Magnetic Resonance, BMRZ), Institute of Organic Chemistry and Chemical Biology, Johann Wolfgang Goethe Universität Frankfurt, Max-von-Laue-Straße 7, 60438, Frankfurt, Germany.
authors.forename: Laurie
authors.initials: L
authors.lastname: Lannes
authors.affiliation: Technische Universität Darmstadt, Clemens-Schöpf-Institut für Organische Chemie und Biochemie, Alarich-Weiss-Straße 4, 64287, Darmstadt, Germany.
authors.forename: Christina Marie
authors.identifier: http://orcid.org/0000-0001-7876-536X
authors.initials: CM
authors.lastname: Thiele
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D004258:DNA Polymerase III / Q000737:chemistry / Q000378:metabolism; D047630:Depsipeptides / Q000737:chemistry* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D047630:Depsipeptides; D010456:Peptides, Cyclic; C000599094:griselimycin; C000599095:methylgriselimycin; C101139:beta subunit, DNA polymerase III; D004258:DNA Polymerase III
keywords: NMR spectroscopy; antibacterials; cyclic peptides; griselimycin; methylgriselimycin; structure determination