5oce

THE MOLECULAR MECHANISM OF SUBSTRATE RECOGNITION AND CATALYSIS OF THE MEMBRANE ACYLTRANSFERASE PatA -- Complex of PatA with palmitate, mannose, and palmitoyl-6-mannose

spinqualitylabelsall models 5oce, resolution 2.41Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5oce is a 4 chain structure with sequence from Mycolicibacterium smegmatis MC2 155. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.41Å Ligands: 9R2, BMA, PLM Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function ACYLT_MYCS2 Catalyzes the acylation to the position 6 of the alpha-1,2-linked mannose residue of the phosphatidyl-myo-inositol dimannoside (PIM2) or monomannoside (PIM1). Publication Abstract from PubMed Glycolipids play a central role in a variety of important biological processes in all living organisms. PatA is a membrane acyltransferase involved in the biosynthesis of phosphatidyl-myo-inositol mannosides (PIMs), key structural elements, and virulence factors of Mycobacterium tuberculosis. PatA catalyzes the transfer of a palmitoyl moiety from palmitoyl-CoA to the 6-position of the mannose ring linked to the 2-position of inositol in PIM1/PIM2. We report here the crystal structure of PatA in the presence of 6-O-palmitoyl-alpha-d-mannopyranoside, unraveling the acceptor binding mechanism. The acceptor mannose ring localizes in a cavity at the end of a surface-exposed long groove where the active site is located, whereas the palmitate moiety accommodates into a hydrophobic pocket deeply buried in the alpha/beta core of the protein. Both fatty acyl chains of the PIM2 acceptor are essential for the reaction to take place, highlighting their critical role in the generation of a competent active site. By the use of combined structural and quantum-mechanics/molecular-mechanics (QM/MM) metadynamics, we unravel the catalytic mechanism of PatA at the atomic-electronic level. Our study provides a detailed structural rationale for a stepwise reaction, with the generation of a tetrahedral transition state for the rate-determining step. Finally, the crystal structure of PatA in the presence of beta-d-mannopyranose and palmitate suggests an inhibitory mechanism for the enzyme, providing exciting possibilities for inhibitor design and the discovery of chemotherapeutic agents against this major human pathogen. The Molecular Mechanism of Substrate Recognition and Catalysis of the Membrane Acyltransferase PatA from Mycobacteria.,Tersa M, Raich L, Albesa-Jove D, Trastoy B, Prandi J, Gilleron M, Rovira C, Guerin ME ACS Chem Biol. 2017 Dec 11. doi: 10.1021/acschembio.7b00578. PMID:29185694 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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