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| {{STRUCTURE_2tmn| PDB=2tmn | SCENE= }} | | {{STRUCTURE_2tmn| PDB=2tmn | SCENE= }} |
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| '''CRYSTALLOGRAPHIC STRUCTURAL ANALYSIS OF PHOSPHORAMIDATES AS INHIBITORS AND TRANSITION-STATE ANALOGS OF THERMOLYSIN'''
| | ===CRYSTALLOGRAPHIC STRUCTURAL ANALYSIS OF PHOSPHORAMIDATES AS INHIBITORS AND TRANSITION-STATE ANALOGS OF THERMOLYSIN=== |
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| ==Overview==
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| The mode of binding to thermolysin of the unsubstituted phosphoramidate inhibitor N-phosphoryl-L-leucinamide (P-Leu-NH2) has been determined crystallographically and refined at high resolution (R = 17.9% to 0.16-nm resolution). The mode of binding of the naturally occurring thermolysin inhibitor phosphoramidon reported previously [Weaver, L. H., Kester, W. R. and Matthews, B. W. (1977) J. Mol. Biol. 114, 119-132] has also been confirmed by crystallographic refinement (R = 17.4% to 0.23-nm resolution). Phosphoramidon binds to the enzyme with a single oxygen of the phosphoramidate moiety as a zinc ligand. Together with three ligands to the metal from the protein the resultant complex has approximately tetrahedral geometry. However, in the case of P-Leu-NH2, two of the phosphoramidate oxygens interact with the zinc to form a complex that tends towards pentacoordinate. In this respect, P-Leu-NH2 appears to be a better transition-state analog than is phosphoramidon. In addition, the phosphorus-nitrogen bond length in P-Leu-NH2 is 0.18 nm, suggesting that the nitrogen is protonated whereas the same bond in phosphoramidon is much shorter (0.15 nm) suggesting that the nitrogen does not carry a charge. In phosphoramidon the distance from the phosphoramide nitrogen to Glu-143 is 0.39 nm whereas in P-Leu-NH2 this distance decreases to 0.34 nm. Taken together, these observations provide additional evidence in support of the participation of pentacoordinate intermediates in the mechanism of action of thermolysin [Holmes, M. A. and Matthews, B. W. (1981) Biochemistry 20, 6912-6920] and the role of Glu-143 in first promoting the attack of a water molecule on the carbonyl carbon of the scissile bond and subsequently acting as a 'proton shuttle' to transfer the proton to the leaving nitrogen [Monzingo, A. F. and Matthews, B. W. (1984) Biochemistry 23, 5724-5729; Hangauer, D. G., Monzingo, A. F. and Matthews, B. W. (1984) Biochemistry 23, 5730-5741].
| | The line below this paragraph, {{ABSTRACT_PUBMED_3709536}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 3709536 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_3709536}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Monzingo, A F.]] | | [[Category: Monzingo, A F.]] |
| [[Category: Tronrud, D E.]] | | [[Category: Tronrud, D E.]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 17:24:48 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 15:03:13 2008'' |
