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| - | [[Image:8cpa.gif|left|200px]] | + | {{Seed}} |
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| | {{STRUCTURE_8cpa| PDB=8cpa | SCENE= }} | | {{STRUCTURE_8cpa| PDB=8cpa | SCENE= }} |
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| - | '''COMPARISON OF THE STRUCTURES OF THREE CARBOXYPEPTIDASE A-PHOSPHONATE COMPLEXES DETERMINED BY X-RAY CRYSTALLOGRAPHY'''
| + | ===COMPARISON OF THE STRUCTURES OF THREE CARBOXYPEPTIDASE A-PHOSPHONATE COMPLEXES DETERMINED BY X-RAY CRYSTALLOGRAPHY=== |
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| - | ==Overview==
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| - | The structures of the complexes of carboxypeptidase A (CPA) with two tight-binding phosphonate inhibitors have been determined by X-ray crystallography. The inhibitors, Cbz-Phe-ValP-(O)-Phe[ZFVP(O)F] and Cbz-Ala-GlyP-(O)-Phe[ZAGP(O)F], bind noncovalently to CPA with dissociation constants (Ki's) of 11 fM and 710 pM, respectively. The CPA-ZFVP(O)F complex crystallizes in the space group P2(1)2(1)2(1) with unit cell parameters a = 65.3 A, b = 63.4 A, and c = 76.0 A, and the CPA-ZAGP(O)F complex crystallizes in the space group P2(1)2(1)2(1) with unit cell parameters a = 63.4 A, b = 65.9 A, and c = 74.4 A. Both structures were determined by molecular replacement to a resolution of 2.0 A. The final crystallographic residuals are 0.189 for the CPA-ZFVP(O)F complex and 0.191 for the CPA-ZAGP(O)F complex. The CPA-ZFVP(O)F complex exhibits the lowest Ki yet determined for an enzyme-inhibitor interaction. Comparison of the CPA-ZFVP(O)F structure with that of the CPA-ZAAP(O)F complex [Kim, H., & Lipscomb, W.N. (1990) Biochemistry 29, 5546-5555] indicates the likely important contributions of hydrophobic and weakly polar enzyme-inhibitor interactions to the exceptional stability of the CPA-ZFVP(O)F complex. Among these interactions is a network of four aromatic rings of CPA and ZFVP(O)F in a configuration that allows stabilizing aromatic-aromatic edge-to-face interactions from one ring to the next. A comparison of the structures of the CPA-ZFVP(O)F, CPA-ZAAP(O)F and CPA-ZAGP(O)F complexes shows that all three phosphonates assume a similar binding mode in the active-site binding groove of CPA. For ZAGP(O)F, the glycyl P1 residue does not lead to an anomalous or a partially disordered binding mode as seen in some previous complexes of CPA involving dipeptide analogue inhibitors with glycyl P1 residues. The additional enzyme-inhibitor interactions for these tripeptide phosphonates secure a binding mode in which a Pi portion of the inhibitor is clearly bound by the corresponding Si binding subsite. These three phosphonates have been implicated as transition-state analogues of the CPA-catalyzed reaction. The phosphinyl groups of these phosphonates coordinate to the active-site zinc in a manner that has been proposed as a characteristic feature of the general-base (Zn-hydroxyl or Zn-water) mechanism for the CPA-catalyzed reaction. Further mechanistic proposals are made for Arg-127, whose probable role in binding substrates is apparent in these CPA-phosphonate complexes.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_1868092}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 1868092 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_1868092}} |
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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 22:49:04 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Jul 11 12:49:48 2008'' |
Revision as of 09:49, 11 July 2008
Template:STRUCTURE 8cpa
COMPARISON OF THE STRUCTURES OF THREE CARBOXYPEPTIDASE A-PHOSPHONATE COMPLEXES DETERMINED BY X-RAY CRYSTALLOGRAPHY
Template:ABSTRACT PUBMED 1868092
About this Structure
8CPA is a Single protein structure of sequence from Bos taurus. Full crystallographic information is available from OCA.
Reference
Comparison of the structures of three carboxypeptidase A-phosphonate complexes determined by X-ray crystallography., Kim H, Lipscomb WN, Biochemistry. 1991 Aug 20;30(33):8171-80. PMID:1868092
Page seeded by OCA on Fri Jul 11 12:49:48 2008
