2afs
From Proteopedia
(New page: 200px<br /> <applet load="2afs" size="450" color="white" frame="true" align="right" spinBox="true" caption="2afs, resolution 2.22Å" /> '''Crystal structure o...) |
|||
| Line 1: | Line 1: | ||
| - | [[Image:2afs.gif|left|200px]]<br /> | + | [[Image:2afs.gif|left|200px]]<br /><applet load="2afs" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="2afs" size=" | + | |
caption="2afs, resolution 2.22Å" /> | caption="2afs, resolution 2.22Å" /> | ||
'''Crystal structure of the genetic mutant R54W of human glutaminyl cyclase'''<br /> | '''Crystal structure of the genetic mutant R54W of human glutaminyl cyclase'''<br /> | ||
==Overview== | ==Overview== | ||
| - | N-terminal pyroglutamate (pGlu) formation from its glutaminyl (or | + | N-terminal pyroglutamate (pGlu) formation from its glutaminyl (or glutamyl) precursor is required in the maturation of numerous bioactive peptides. The aberrant formation of pGlu may be related to several pathological processes, such as osteoporosis and amyloidotic diseases. This N-terminal cyclization reaction, once thought to proceed spontaneously, is greatly facilitated by the enzyme glutaminyl cyclase (QC). To probe this important but poorly understood modification, we present here the structure of human QC in free form and bound to a substrate and three imidazole-derived inhibitors. The structure reveals an alpha/beta scaffold akin to that of two-zinc exopeptidases but with several insertions and deletions, particularly in the active-site region. The relatively closed active site displays alternate conformations due to the different indole orientations of Trp-207, resulting in two substrate (glutamine t-butyl ester)-binding modes. The single zinc ion in the active site is coordinated to three conserved residues and one water molecule, which is replaced by an imidazole nitrogen upon binding of the inhibitors. Together with structural and kinetic analyses of several active-site-mutant enzymes, a catalysis mechanism of the formation of protein N-terminal pGlu is proposed. Our results provide a structural basis for the rational design of inhibitors against QC-associated disorders. |
==About this Structure== | ==About this Structure== | ||
| - | 2AFS is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with ZN and SO4 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Glutaminyl-peptide_cyclotransferase Glutaminyl-peptide cyclotransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.2.5 2.3.2.5] Full crystallographic information is available from [http:// | + | 2AFS is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=ZN:'>ZN</scene> and <scene name='pdbligand=SO4:'>SO4</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Glutaminyl-peptide_cyclotransferase Glutaminyl-peptide cyclotransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.2.5 2.3.2.5] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2AFS OCA]. |
==Reference== | ==Reference== | ||
| Line 15: | Line 14: | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Cheng, W | + | [[Category: Cheng, W J.]] |
| - | [[Category: Huang, K | + | [[Category: Huang, K F.]] |
| - | [[Category: Ko, T | + | [[Category: Ko, T P.]] |
| - | [[Category: Liu, Y | + | [[Category: Liu, Y L.]] |
| - | [[Category: Wang, A | + | [[Category: Wang, A H.J.]] |
[[Category: SO4]] | [[Category: SO4]] | ||
[[Category: ZN]] | [[Category: ZN]] | ||
| Line 25: | Line 24: | ||
[[Category: metalloprotein]] | [[Category: metalloprotein]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:27:03 2008'' |
Revision as of 14:27, 21 February 2008
|
Crystal structure of the genetic mutant R54W of human glutaminyl cyclase
Overview
N-terminal pyroglutamate (pGlu) formation from its glutaminyl (or glutamyl) precursor is required in the maturation of numerous bioactive peptides. The aberrant formation of pGlu may be related to several pathological processes, such as osteoporosis and amyloidotic diseases. This N-terminal cyclization reaction, once thought to proceed spontaneously, is greatly facilitated by the enzyme glutaminyl cyclase (QC). To probe this important but poorly understood modification, we present here the structure of human QC in free form and bound to a substrate and three imidazole-derived inhibitors. The structure reveals an alpha/beta scaffold akin to that of two-zinc exopeptidases but with several insertions and deletions, particularly in the active-site region. The relatively closed active site displays alternate conformations due to the different indole orientations of Trp-207, resulting in two substrate (glutamine t-butyl ester)-binding modes. The single zinc ion in the active site is coordinated to three conserved residues and one water molecule, which is replaced by an imidazole nitrogen upon binding of the inhibitors. Together with structural and kinetic analyses of several active-site-mutant enzymes, a catalysis mechanism of the formation of protein N-terminal pGlu is proposed. Our results provide a structural basis for the rational design of inhibitors against QC-associated disorders.
About this Structure
2AFS is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Glutaminyl-peptide cyclotransferase, with EC number 2.3.2.5 Full crystallographic information is available from OCA.
Reference
Crystal structures of human glutaminyl cyclase, an enzyme responsible for protein N-terminal pyroglutamate formation., Huang KF, Liu YL, Cheng WJ, Ko TP, Wang AH, Proc Natl Acad Sci U S A. 2005 Sep 13;102(37):13117-22. Epub 2005 Aug 31. PMID:16135565
Page seeded by OCA on Thu Feb 21 16:27:03 2008
