5lif | pdb_00005lif

Thermolysin in complex with inhibitor

spinqualitylabelsall models 5lif, resolution 1.31Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5lif is a 1 chain structure with sequence from Bacillus thermoproteolyticus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.31Å Ligands: 6XO, CA, DMS, GOL, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function THER_BACTH Extracellular zinc metalloprotease. Publication Abstract from PubMed Kinetic parameters of protein-ligand interactions are progressively acknowledged as valuable information for rational drug discovery. However, a targeted optimization of binding kinetics is not easy to achieve, and further systematic studies are necessary to increase the understanding about molecular mechanisms involved. We determined association and dissociation rate constants for 17 inhibitors of the metalloprotease thermolysin by surface plasmon resonance spectroscopy and correlated kinetic data with high-resolution crystal structures in complex with the protein. From the structure-kinetics relationship, we conclude that the strength of interaction with Asn112 correlates with the rate-limiting step of dissociation. This residue is located at the beginning of a beta-strand motif that lines the binding cleft and is commonly believed to align a substrate for catalysis. A reduced mobility of the Asn112 side chain owing to an enhanced engagement in charge-assisted hydrogen bonds prevents the conformational adjustment associated with ligand release and transformation of the enzyme to its open state. This hypothesis is supported by kinetic data of ZFPLA, a known pseudopeptidic inhibitor of thermolysin, which blocks the conformational transition of Asn112. Interference with this retrograde induced-fit mechanism results in variation of the residence time of thermolysin inhibitors by a factor of 74000. The high conservation of this structural motif within the M4 and M13 metalloprotease families underpins the importance of this feature and has significant implications for drug discovery. Elucidating the Origin of Long Residence Time Binding for Inhibitors of the Metalloprotease Thermolysin.,Cramer J, Krimmer SG, Fridh V, Wulsdorf T, Karlsson R, Heine A, Klebe G ACS Chem Biol. 2016 Dec 13. PMID:27959500 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Thermolysin 3D structures

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