5i8w

Crystal structure of B. pseudomallei FabI in complex with NAD and PT401

spinqualitylabelsall models 5i8w, resolution 1.63Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5i8w is a 1 chain structure with sequence from Burkholderia pseudomallei. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.629Å Ligands: 69H, NAD Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A0A0H3HP34_BURP2 Publication Abstract from PubMed There is growing awareness of the link between drug-target residence time and in vivo drug activity, and there are increasing efforts to determine the molecular factors that control the lifetime of a drug-target complex. Rational alterations in drug-target residence time require knowledge of both the ground and transition states on the inhibition reaction coordinate, and we have determined the structure-kinetic relationship for 22 ethyl or hexyl substituted diphenyl ethers that are slow-binding inhibitors of bpFabI1, the enoyl-ACP reductase FabI1 from Burkholderia pseudomallei. Analysis of enzyme inhibition using a 2D-kinetic map demonstrates that the ethyl and hexyl diphenyl ethers fall into two distinct clusters. Modifications to the ethyl diphenyl ether B ring result in changes to both on and off-rates, where residence times of up to ~700 min (~11 h) are achieved by either ground state stabilization (PT444) or transition state destabilization (slower on-rate) (PT404). By contrast, modifications to the hexyl diphenyl ether B ring result in residence times of 300 min (~5 h) through changes in only ground state stabilization (PT119). Structural analysis of 9 enzyme:inhibitor complexes reveal that the variation in structure-kinetic relationships can be rationalized by structural rearrangements of bpFabI1 and subtle changes to the orientation of the inhibitor in the binding pocket. Finally, we demonstrate that three compounds with residence times on bpFabI1 of between 118 min (~2 h) and 670 min (~11 h) have in vivo efficacy in an acute B. pseudomallei murine infection model using the virulent B. pseudomallei strain Bp400. Rational Optimization of Diphenyl Ether Binding Kinetics to the Enoyl-ACP Reductase FabI1 from Burkholderia pseudomallei.,Neckles CM, Eltschkner S, Cummings JE, Hirschbeck M, Daryaee F, Bommineni GR, Zhang Z, Spagnuolo LA, Yu W, Davoodi S, Slayden RA, Kisker C, Tonge PJ Biochemistry. 2017 Feb 22. doi: 10.1021/acs.biochem.6b01048. PMID:28225601 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Enoyl-Acyl-Carrier Protein Reductase 3D structures

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