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| | {{STRUCTURE_6cpa| PDB=6cpa | SCENE= }} | | {{STRUCTURE_6cpa| PDB=6cpa | SCENE= }} |
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| - | '''CRYSTAL STRUCTURE OF THE COMPLEX OF CARBOXYPEPTIDASE A WITH A STRONGLY BOUND PHOSPHONATE IN A NEW CRYSTALLINE FORM: COMPARISON WITH STRUCTURES OF OTHER COMPLEXES'''
| + | ===CRYSTAL STRUCTURE OF THE COMPLEX OF CARBOXYPEPTIDASE A WITH A STRONGLY BOUND PHOSPHONATE IN A NEW CRYSTALLINE FORM: COMPARISON WITH STRUCTURES OF OTHER COMPLEXES=== |
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| - | ==Overview==
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| - | O-[[(1R)-[[N-(Phenylmethoxycarbonyl)-L-alanyl]amino]ethyl] hydroxyphosphinyl]-L-3-phenyllacetate [ZAAP(O)F], an analogue of (benzyloxycarbonyl)-Ala-Ala-Phe or (benzyloxycarbonyl)-Ala-Ala-phenyllactate, binds to carboxypeptidase A with great affinity (Ki = 3 pM). Similar phosphonates have been shown to be transition-state analogues of the CPA-catalyzed hydrolysis [Hanson, J. E., Kaplan, A. P., & Bartlett, P. A. (1989) Biochemistry 28, 6294-6305]. In the present study, the structure of the complex of this phosphonate with carboxypeptidase A has been determined by X-ray crystallography to a resolution of 2.0 A. The complex crystallizes in the space group P2(1)2(1)2(1) with cell dimensions a = 61.9 A, b = 67.2 A, and c = 76.2 A. The structure of the complex was solved by molecular replacement. Refinement of the structure against 20,776 unique reflections between 10.0 and 2.0 A yields a crystallographic residual of 0.193, including 140 water molecules. The two phosphinyl oxygens of the inhibitor bind to the active-site zinc at 2.2 A on the electrophilic (Arg-127) side and 3.1 A on the nucleophilic (Glu-270) side. Various features of the binding mode of this phosphonate inhibitor are consistent with the hypothesis that carboxypeptidase A catalyzed hydrolysis proceeds through a general-base mechanism in which the carbonyl carbon of the substrate is attacked by Zn-hydroxyl (or Zn-water). An unexpected feature of the bound inhibitor, the cis carbamoyl ester bond at the benzyloxycarbonyl linkage to alanine, allows the benzyloxycarbonyl phenyl ring of the inhibitor to interact favorably with Tyr-198. This complex structure is compared with previous structures of carboxypeptidase A, including the complexes with the potato inhibitor, a hydrated keto methylene substrate analogue, and a phosphonamidate inhibitor. Comparisons are also made with the complexes of thermolysin with some phosphonamidate inhibitors.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_2386784}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 2386784 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_2386784}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Kim, H.]] | | [[Category: Kim, H.]] |
| | [[Category: Lipscomb, W N.]] | | [[Category: Lipscomb, W N.]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 22:39:48 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Jul 3 14:16:41 2008'' |
Revision as of 11:16, 3 July 2008
Template:STRUCTURE 6cpa
CRYSTAL STRUCTURE OF THE COMPLEX OF CARBOXYPEPTIDASE A WITH A STRONGLY BOUND PHOSPHONATE IN A NEW CRYSTALLINE FORM: COMPARISON WITH STRUCTURES OF OTHER COMPLEXES
Template:ABSTRACT PUBMED 2386784
About this Structure
6CPA is a Single protein structure of sequence from Bos taurus. Full crystallographic information is available from OCA.
Reference
Crystal structure of the complex of carboxypeptidase A with a strongly bound phosphonate in a new crystalline form: comparison with structures of other complexes., Kim H, Lipscomb WN, Biochemistry. 1990 Jun 12;29(23):5546-55. PMID:2386784
Page seeded by OCA on Thu Jul 3 14:16:41 2008
