7cpa
From Proteopedia
(New page: 200px<br /><applet load="7cpa" size="450" color="white" frame="true" align="right" spinBox="true" caption="7cpa, resolution 2.0Å" /> '''COMPARISON OF THE STR...) |
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| - | [[Image:7cpa.gif|left|200px]]<br /><applet load="7cpa" size=" | + | [[Image:7cpa.gif|left|200px]]<br /><applet load="7cpa" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="7cpa, resolution 2.0Å" /> | caption="7cpa, resolution 2.0Å" /> | ||
'''COMPARISON OF THE STRUCTURES OF THREE CARBOXYPEPTIDASE A-PHOSPHONATE COMPLEXES DETERMINED BY X-RAY CRYSTALLOGRAPHY'''<br /> | '''COMPARISON OF THE STRUCTURES OF THREE CARBOXYPEPTIDASE A-PHOSPHONATE COMPLEXES DETERMINED BY X-RAY CRYSTALLOGRAPHY'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The structures of the complexes of carboxypeptidase A (CPA) with two | + | 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. |
==About this Structure== | ==About this Structure== | ||
| - | 7CPA is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] with ZN and FVF as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Carboxypeptidase_A Carboxypeptidase A], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.17.1 3.4.17.1] Full crystallographic information is available from [http:// | + | 7CPA is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] with <scene name='pdbligand=ZN:'>ZN</scene> and <scene name='pdbligand=FVF:'>FVF</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Carboxypeptidase_A Carboxypeptidase A], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.17.1 3.4.17.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7CPA OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Kim, H.]] | [[Category: Kim, H.]] | ||
| - | [[Category: Lipscomb, W | + | [[Category: Lipscomb, W N.]] |
[[Category: FVF]] | [[Category: FVF]] | ||
[[Category: ZN]] | [[Category: ZN]] | ||
[[Category: hydrolase(c-terminal peptidase)]] | [[Category: hydrolase(c-terminal peptidase)]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 19:17:01 2008'' |
Revision as of 17:17, 21 February 2008
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COMPARISON OF THE STRUCTURES OF THREE CARBOXYPEPTIDASE A-PHOSPHONATE COMPLEXES DETERMINED BY X-RAY CRYSTALLOGRAPHY
Overview
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.
About this Structure
7CPA is a Single protein structure of sequence from Bos taurus with and as ligands. Active as Carboxypeptidase A, with EC number 3.4.17.1 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
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