1pzp | pdb_00001pzp

TEM-1 Beta-Lactamase in Complex with a Novel, Core-Disrupting, Allosteric Inhibitor

spinqualitylabelsall models 1pzp, resolution 1.45Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 1pzp is a 1 chain structure with sequence from Escherichia coli. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.45Å Ligands: FTA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function BLAT_ECOLX TEM-type are the most prevalent beta-lactamases in enterobacteria; they hydrolyze the beta-lactam bond in susceptible beta-lactam antibiotics, thus conferring resistance to penicillins and cephalosporins. TEM-3 and TEM-4 are capable of hydrolyzing cefotaxime and ceftazidime. TEM-5 is capable of hydrolyzing ceftazidime. TEM-6 is capable of hydrolyzing ceftazidime and aztreonam. TEM-8/CAZ-2, TEM-16/CAZ-7 and TEM-24/CAZ-6 are markedly active against ceftazidime. IRT-4 shows resistance to beta-lactamase inhibitors. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed Although inhibitors typically bind pre-formed sites on proteins, it is theoretically possible to inhibit by disrupting the folded structure of a protein or, in the limit, to bind preferentially to the unfolded state. Equilibria defining how such molecules act are well understood, but structural models for such binding are unknown. Two novel inhibitors of beta-lactamase were found to destabilize the enzyme at high temperatures, but at lower temperatures showed no preference for destabilized mutant enzymes versus stabilized mutants. X-ray crystal structures showed that both inhibitors bound to a cryptic site in beta-lactamase, which the inhibitors themselves created by forcing apart helixes 11 and 12. This opened up a portion of the hydrophobic core of the protein, into which these two inhibitors bind. Although this binding site is 16 A from the center of the active site, the conformational changes were transmitted through a sequence of linked motions to a key catalytic residue, Arg244, which in the complex adopts conformations very different from those in catalytically competent enzyme conformations. These structures offer a detailed view of what has heretofore been a theoretical construct, and suggest the possibility for further design against this novel site. Allosteric inhibition through core disruption.,Horn JR, Shoichet BK J Mol Biol. 2004 Mar 5;336(5):1283-91. PMID:15037085 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Beta-lactamase 3D structures

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