1PZO
TEM-1 Beta-Lactamase in Complex with a Novel, Core-Disrupting, Allosteric Inhibitor
Summary for 1PZO
| Entry DOI | 10.2210/pdb1pzo/pdb |
| Related | 1PZP |
| Descriptor | Beta-lactamase TEM, N,N-BIS(4-CHLOROBENZYL)-1H-1,2,3,4-TETRAAZOL-5-AMINE (3 entities in total) |
| Functional Keywords | beta-lactamase, novel allosteric inhibitor, core-disruption, hydrolase |
| Biological source | Escherichia coli |
| Total number of polymer chains | 1 |
| Total formula weight | 29580.31 |
| Authors | Horn, J.R.,Shoichet, B.K. (deposition date: 2003-07-14, release date: 2004-03-09, Last modification date: 2024-11-20) |
| Primary citation | Horn, J.R.,Shoichet, B.K. Allosteric inhibition through core disruption. J.Mol.Biol., 336:1283-1291, 2004 Cited by PubMed Abstract: 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. PubMed: 15037085DOI: 10.1016/j.jmb.2003.12.068 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
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