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| | {{STRUCTURE_1blh| PDB=1blh | SCENE= }} | | {{STRUCTURE_1blh| PDB=1blh | SCENE= }} |
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| - | '''STRUCTURE OF A PHOSPHONATE-INHIBITED BETA-LACTAMASE. AN ANALOG OF THE TETRAHEDRAL TRANSITION STATE(SLASH)INTERMEDIATE OF BETA-LACTAM HYDROLYSIS'''
| + | ===STRUCTURE OF A PHOSPHONATE-INHIBITED BETA-LACTAMASE. AN ANALOG OF THE TETRAHEDRAL TRANSITION STATE(SLASH)INTERMEDIATE OF BETA-LACTAM HYDROLYSIS=== |
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| - | ==Overview==
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| - | The crystal structure of beta-lactamase from Staphylococcus aureus inactivated by p-nitrophenyl[[N-(benzyloxycarbonyl)amino]methyl]phosphonate, a methylphosphonate monoester monoanion inhibitor, has been determined and refined at 2.3 A resolution. The structure reveals a tetrahedral phosphorus covalently bonded to the O gamma atom of the active site serine, Ser70. One of the oxygen atoms bonded to phosphorus is located in the oxyanion hole formed by the two main-chain nitrogen atoms of Ser70 and Gln237, and the second bonded oxygen is solvated. The (benzyloxycarbonyl)aminomethyl group is oriented towards the active site gully such that the peptide group forms compensating electrostatic interactions with polar groups on the enzyme. The benzyl group forms a hydrophobic interaction with Ile239 and an aromatic-aromatic edge-to-face interaction with Tyr105, which has undergone a conformational transition relative to the native structure. The mode of binding supports the proposal that on reaction with the enzyme, the phosphonate generates a structure analogous to the tetrahedral transition state/intermediate associated with the acylation step of a normal substrate. The disposition of the phosphonyl group in this complex is the same as that of the corresponding phosphoryl group in the complex resulting from the inhibition of trypsin by diisopropylphosphofluoridate. The structure is consistent with a mechanism of inactivation that follows an associative pathway, proceeding via a transition state/intermediate in which phosphorus is penta-co-ordinated, forming a trigonal bipyramidal geometry with the phosphonyl donor (p-nitrophenol) and acceptor (Ser70 O gamma atom) in apical positions. A model of this transition state can be accommodated in the active site of beta-lactamase without any steric hindrance. A model of the tetrahedral transition state associated with the acylation step by benzyl penicillin has been derived. Because of the conformational rigidity of the fused rings of penicillin molecules, the orientation of the substrate is fixed once the tetrahedral carbonyl carbon and its ligands are superimposed on the phosphonate group. The outcome is that the carboxylate substituent on the thiazolidine ring forms a salt bridge with Lys234, and the preferred puckering of the ring is that observed in the crystal structure of ampicillin, the so-called "open" conformer. | + | The line below this paragraph, {{ABSTRACT_PUBMED_8230196}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 8230196 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_8230196}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Chen, C C.H.]] | | [[Category: Chen, C C.H.]] |
| | [[Category: Herzberg, O.]] | | [[Category: Herzberg, O.]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 11:40:10 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jun 30 19:20:58 2008'' |
Revision as of 16:21, 30 June 2008
Template:STRUCTURE 1blh
STRUCTURE OF A PHOSPHONATE-INHIBITED BETA-LACTAMASE. AN ANALOG OF THE TETRAHEDRAL TRANSITION STATE(SLASH)INTERMEDIATE OF BETA-LACTAM HYDROLYSIS
Template:ABSTRACT PUBMED 8230196
About this Structure
1BLH is a Single protein structure of sequence from Staphylococcus aureus. Full crystallographic information is available from OCA.
Reference
Structure of a phosphonate-inhibited beta-lactamase. An analog of the tetrahedral transition state/intermediate of beta-lactam hydrolysis., Chen CC, Rahil J, Pratt RF, Herzberg O, J Mol Biol. 1993 Nov 5;234(1):165-78. PMID:8230196
Page seeded by OCA on Mon Jun 30 19:20:58 2008
