1f57
From Proteopedia
(New page: 200px<br /><applet load="1f57" size="450" color="white" frame="true" align="right" spinBox="true" caption="1f57, resolution 1.75Å" /> '''CARBOXYPEPTIDASE A C...) |
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| - | [[Image:1f57.jpg|left|200px]]<br /><applet load="1f57" size=" | + | [[Image:1f57.jpg|left|200px]]<br /><applet load="1f57" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1f57, resolution 1.75Å" /> | caption="1f57, resolution 1.75Å" /> | ||
'''CARBOXYPEPTIDASE A COMPLEX WITH D-CYSTEINE AT 1.75 A'''<br /> | '''CARBOXYPEPTIDASE A COMPLEX WITH D-CYSTEINE AT 1.75 A'''<br /> | ||
==Overview== | ==Overview== | ||
| - | D-Cysteine differs from the antiarthritis drug D-penicillamine by only two | + | D-Cysteine differs from the antiarthritis drug D-penicillamine by only two methyl groups on the beta-carbon yet inhibits carboxypeptidase A (CPD) by a distinct mechanism: D-cysteine binds tightly to the active site zinc, while D-penicillamine catalyzes metal removal. To investigate the structural basis for this difference, we solved the crystal structure of carboxypeptidase A complexed with D-cysteine (D-Cys) at 1.75-A resolution. D-Cys binds the active site zinc with a sulfur ligand and forms additional interactions with surrounding side chains of the enzyme. The structure explains the difference in potency between D-Cys and L-Cys and provides insight into the mechanism of D-penicillamine inhibition. D-Cys binding induces a concerted motion of the side chains around the zinc ion, similar to that found in other carboxypeptidase-inhibitor crystal structures and along a limited path. Analysis of concerted motions of CPD and CPD-inhibitor crystal structures reveals a clustering of these structures into distinct groups. Using the restricted conformational flexibility of a drug target in this type of analysis could greatly enhance efficiency in drug design. |
==About this Structure== | ==About this Structure== | ||
| - | 1F57 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 DCY 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:// | + | 1F57 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=DCY:'>DCY</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=1F57 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Carboxypeptidase A]] | [[Category: Carboxypeptidase A]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Aalten, D | + | [[Category: Aalten, D M.van.]] |
| - | [[Category: Chong, C | + | [[Category: Chong, C R.]] |
[[Category: Joshua-Tor, L.]] | [[Category: Joshua-Tor, L.]] | ||
[[Category: DCY]] | [[Category: DCY]] | ||
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[[Category: metalloprotease inhibitor]] | [[Category: metalloprotease inhibitor]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:34:59 2008'' |
Revision as of 10:34, 21 February 2008
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CARBOXYPEPTIDASE A COMPLEX WITH D-CYSTEINE AT 1.75 A
Overview
D-Cysteine differs from the antiarthritis drug D-penicillamine by only two methyl groups on the beta-carbon yet inhibits carboxypeptidase A (CPD) by a distinct mechanism: D-cysteine binds tightly to the active site zinc, while D-penicillamine catalyzes metal removal. To investigate the structural basis for this difference, we solved the crystal structure of carboxypeptidase A complexed with D-cysteine (D-Cys) at 1.75-A resolution. D-Cys binds the active site zinc with a sulfur ligand and forms additional interactions with surrounding side chains of the enzyme. The structure explains the difference in potency between D-Cys and L-Cys and provides insight into the mechanism of D-penicillamine inhibition. D-Cys binding induces a concerted motion of the side chains around the zinc ion, similar to that found in other carboxypeptidase-inhibitor crystal structures and along a limited path. Analysis of concerted motions of CPD and CPD-inhibitor crystal structures reveals a clustering of these structures into distinct groups. Using the restricted conformational flexibility of a drug target in this type of analysis could greatly enhance efficiency in drug design.
About this Structure
1F57 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
Crystal structure of carboxypeptidase A complexed with D-cysteine at 1.75 A - inhibitor-induced conformational changes., van Aalten DM, Chong CR, Joshua-Tor L, Biochemistry. 2000 Aug 22;39(33):10082-9. PMID:10955996
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