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| | {{STRUCTURE_1mpl| PDB=1mpl | SCENE= }} | | {{STRUCTURE_1mpl| PDB=1mpl | SCENE= }} |
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| - | '''CRYSTAL STRUCTURE OF PHOSPHONATE-INHIBITED D-ALA-D-ALA PEPTIDASE REVEALS AN ANALOG OF A TETRAHEDRAL TRANSITION STATE'''
| + | ===CRYSTAL STRUCTURE OF PHOSPHONATE-INHIBITED D-ALA-D-ALA PEPTIDASE REVEALS AN ANALOG OF A TETRAHEDRAL TRANSITION STATE=== |
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| - | ==Overview==
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| - | D-Alanyl-D-alanine carboxypeptidase/transpeptidases (DD-peptidases) are beta-lactam-sensitive enzymes that are responsible for the final peptidoglycan cross-linking step in bacterial cell wall biosynthesis. A highly specific tripeptide phosphonate inhibitor was designed with a side chain corresponding to a portion of the Streptomyces R61 peptidoglycan. This compound was found to be a slow, irreversible inactivator of the DD-peptidase. Molecular modeling suggested that although a pentacoordinated intermediate of the phosphonylation reaction would not interact strongly with the enzyme, a tetracoordinated phosphonyl enzyme might be analogous to a transition state in the reaction with peptide substrates. To investigate this possibility, the crystal structure of the phosphonyl enzyme was determined. The 1.1 A resolution structure shows that the inhibitor has phosphonylated the catalytic serine (Ser62). One of the phosphonyl oxygens is noncovalently bound in the oxyanion hole, while the other is solvated by two water molecules. The conserved hydroxyl group of Tyr159 forms a strong hydrogen bond with the latter oxygen atom (2.77 A). This arrangement is interpreted as being analogous to the transition state for the formation of the tetrahedral intermediate in the deacylation step of the carboxypeptidase reaction. The proximity of Tyr159 to the solvated phosphonyl oxygen suggests that the tyrosine anion acts as a general base for deacylation. This transition state analogue structure is compared to the structures of noncovalent DD-peptidase reaction intermediates and phosphonylated beta-lactamases. These comparisons show that specific substrate binding to the peptidase induces a conformational change in the active site that places Ser62 in an optimal position for catalysis. This activated conformation relaxes as the reaction proceeds.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_12564922}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 12564922 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_12564922}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Peptidoglycan]] | | [[Category: Peptidoglycan]] |
| | [[Category: Transition state analog]] | | [[Category: Transition state analog]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 01:33:42 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Jul 3 00:42:22 2008'' |
Revision as of 21:42, 2 July 2008
Template:STRUCTURE 1mpl
CRYSTAL STRUCTURE OF PHOSPHONATE-INHIBITED D-ALA-D-ALA PEPTIDASE REVEALS AN ANALOG OF A TETRAHEDRAL TRANSITION STATE
Template:ABSTRACT PUBMED 12564922
About this Structure
1MPL is a Single protein structure of sequence from Streptomyces sp.. Full crystallographic information is available from OCA.
Reference
The crystal structure of phosphonate-inhibited D-Ala-D-Ala peptidase reveals an analogue of a tetrahedral transition state., Silvaggi NR, Anderson JW, Brinsmade SR, Pratt RF, Kelly JA, Biochemistry. 2003 Feb 11;42(5):1199-208. PMID:12564922
Page seeded by OCA on Thu Jul 3 00:42:22 2008
