title: Combined molecular dynamics, STD-NMR, and CORCEMA protocol yields structural model for a UDP-galactopyranose mutase-inhibitor complex.
abstract: UDP-galactopyranose mutase (UGM) is an enzyme involved in the biosynthesis of the Mycobacterium tuberculosis cell wall, and is essential for the growth and survival of the organism. A micromolar inhibitor developed by tetrafluorination of the UGM substrate has been previously studied by saturation transfer difference (STD) NMR spectroscopy. To elucidate the bioactive conformation of the inhibitor bound to UGM, we employ molecular dynamics (MD) simulations to construct a structural model. The MD model is subsequently validated by a good fit between experimental and theoretical STD effects, the latter calculated by a complete relaxation and conformational exchange matrix (CORCEMA) analysis. This structural model is used to explain the relative binding affinities of the inhibitor and the parent substrate.
authors: Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada. Electronic address: shiyuns@sfu.ca.
authors: Yun
authors: Y
authors: Shi
authors: Department of Chemistry, Centro de Investigaciones Biológicas (CIB-CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain. Electronic address: aarda@cib.csic.es.
authors: Ana
authors: A
authors: Ardá
authors: Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada. Electronic address: bpinto@sfu.ca.
authors: B Mario
authors: BM
authors: Pinto
mesh_terms: D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007711:Klebsiella pneumoniae / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary
chemical_list: D004791:Enzyme Inhibitors; D019751:Intramolecular Transferases; C098051:UDP-galactopyranose mutase
keywords: CORCEMA; MD simulations; Saturation transfer difference; Structural model; UGM–inhibitor complex