2evc
From Proteopedia
(New page: 200px<br /><applet load="2evc" size="450" color="white" frame="true" align="right" spinBox="true" caption="2evc, resolution 1.6Å" /> '''Crystal structure of ...) |
|||
| Line 1: | Line 1: | ||
| - | [[Image:2evc.gif|left|200px]]<br /><applet load="2evc" size=" | + | [[Image:2evc.gif|left|200px]]<br /><applet load="2evc" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="2evc, resolution 1.6Å" /> | caption="2evc, resolution 1.6Å" /> | ||
'''Crystal structure of E. Coli. methionine amino peptidase in complex with 5-(2-(trifluoromethyl)phenyl)furan-2-carboxylic acid'''<br /> | '''Crystal structure of E. Coli. methionine amino peptidase in complex with 5-(2-(trifluoromethyl)phenyl)furan-2-carboxylic acid'''<br /> | ||
==Overview== | ==Overview== | ||
| - | One of the challenges in the development of methionine aminopeptidase | + | One of the challenges in the development of methionine aminopeptidase (MetAP) inhibitors as antibacterial and anticancer agents is to define the metal ion actually used by MetAP in vivo and to discover MetAP inhibitors that can inhibit the metalloform that is relevant in vivo. Two distinct classes of novel nonpeptidic MetAP inhibitors that are not only potent but also highly selective for either the Mn(II) or Co(II) form have been identified. Three crystal structures of Escherichia coli MetAP complexed with the metalloform-selective inhibitors 5-(2,5-dichlorophenyl)furan-2-carboxylic acid (2), 5-[2-(trifluoromethyl)phenyl]furan-2-carboxylic acid (3) and N-cyclopentyl-N-(thiazol-2-yl)oxalamide (4) have been solved and analysis of these structures has revealed the structural basis for their metalloform-selective inhibition. The Mn(II)-form selective inhibitors (2) and (3) both use their carboxylate group to coordinate with the two Mn(II) ions at the dinuclear metal site and both adopt a non-coplanar conformation for the two aromatic rings. The unique coordination geometry of these inhibitors may determine their Mn(II)-form selectivity. In contrast, the Co(II)-form selective inhibitor (4) recruits an unexpected third metal ion, forming a trimetallic enzyme-metal-inhibitor complex. Thus, an important factor in the selectivity of (4) for the Co(II) form may be a consequence of a greater preference for a softer N,O-donor ligand for the softer Co(II). |
==About this Structure== | ==About this Structure== | ||
| - | 2EVC is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with MN, NA and FC3 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Methionyl_aminopeptidase Methionyl aminopeptidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.11.18 3.4.11.18] Full crystallographic information is available from [http:// | + | 2EVC is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with <scene name='pdbligand=MN:'>MN</scene>, <scene name='pdbligand=NA:'>NA</scene> and <scene name='pdbligand=FC3:'>FC3</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Methionyl_aminopeptidase Methionyl aminopeptidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.11.18 3.4.11.18] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2EVC OCA]. |
==Reference== | ==Reference== | ||
| Line 14: | Line 14: | ||
[[Category: Methionyl aminopeptidase]] | [[Category: Methionyl aminopeptidase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Huang, W | + | [[Category: Huang, W J.]] |
[[Category: FC3]] | [[Category: FC3]] | ||
[[Category: MN]] | [[Category: MN]] | ||
| Line 21: | Line 21: | ||
[[Category: methionine amino peptidase]] | [[Category: methionine amino peptidase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:14:56 2008'' |
Revision as of 15:14, 21 February 2008
|
Crystal structure of E. Coli. methionine amino peptidase in complex with 5-(2-(trifluoromethyl)phenyl)furan-2-carboxylic acid
Overview
One of the challenges in the development of methionine aminopeptidase (MetAP) inhibitors as antibacterial and anticancer agents is to define the metal ion actually used by MetAP in vivo and to discover MetAP inhibitors that can inhibit the metalloform that is relevant in vivo. Two distinct classes of novel nonpeptidic MetAP inhibitors that are not only potent but also highly selective for either the Mn(II) or Co(II) form have been identified. Three crystal structures of Escherichia coli MetAP complexed with the metalloform-selective inhibitors 5-(2,5-dichlorophenyl)furan-2-carboxylic acid (2), 5-[2-(trifluoromethyl)phenyl]furan-2-carboxylic acid (3) and N-cyclopentyl-N-(thiazol-2-yl)oxalamide (4) have been solved and analysis of these structures has revealed the structural basis for their metalloform-selective inhibition. The Mn(II)-form selective inhibitors (2) and (3) both use their carboxylate group to coordinate with the two Mn(II) ions at the dinuclear metal site and both adopt a non-coplanar conformation for the two aromatic rings. The unique coordination geometry of these inhibitors may determine their Mn(II)-form selectivity. In contrast, the Co(II)-form selective inhibitor (4) recruits an unexpected third metal ion, forming a trimetallic enzyme-metal-inhibitor complex. Thus, an important factor in the selectivity of (4) for the Co(II) form may be a consequence of a greater preference for a softer N,O-donor ligand for the softer Co(II).
About this Structure
2EVC is a Single protein structure of sequence from Escherichia coli with , and as ligands. Active as Methionyl aminopeptidase, with EC number 3.4.11.18 Full crystallographic information is available from OCA.
Reference
Structural analysis of metalloform-selective inhibition of methionine aminopeptidase., Xie SX, Huang WJ, Ma ZQ, Huang M, Hanzlik RP, Ye QZ, Acta Crystallogr D Biol Crystallogr. 2006 Apr;62(Pt 4):425-32. Epub 2006, Mar 18. PMID:16552144
Page seeded by OCA on Thu Feb 21 17:14:56 2008
