1pkx
From Proteopedia
(New page: 200px<br /> <applet load="1pkx" size="450" color="white" frame="true" align="right" spinBox="true" caption="1pkx, resolution 1.90Å" /> '''Crystal Structure o...) |
|||
| Line 1: | Line 1: | ||
| - | [[Image:1pkx.gif|left|200px]]<br /> | + | [[Image:1pkx.gif|left|200px]]<br /><applet load="1pkx" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1pkx" size=" | + | |
caption="1pkx, resolution 1.90Å" /> | caption="1pkx, resolution 1.90Å" /> | ||
'''Crystal Structure of human ATIC in complex with XMP'''<br /> | '''Crystal Structure of human ATIC in complex with XMP'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Within de novo purine biosynthesis, the AICAR transformylase and IMP | + | Within de novo purine biosynthesis, the AICAR transformylase and IMP cyclohydrolase activities of the bifunctional enzyme ATIC convert the intermediate AICAR to the final product of the pathway, IMP. Identification of the AICAR transformylase active site and a proposed formyl transfer mechanism have already resulted from analysis of crystal structures of avian ATIC in complex with substrate and/or inhibitors. Herein, we focus on the IMPCH active site and the cyclohydrolase mechanism through comparison of crystal structures of XMP inhibitor complexes of human ATIC at 1.9 A resolution with the previously determined avian enzyme. This first human ATIC structure was also determined to ascertain whether any subtle structural differences, compared to the homologous avian enzyme, should be taken into account for structure-based inhibitor design. These structural comparisons, as well as comparative analyses with other IMP and XMP binding proteins, have enabled a catalytic mechanism to be formulated. The primary role of the IMPCH active site appears to be to induce a reconfiguration of the substrate FAICAR to a less energetically favorable, but more reactive, conformer. Backbone (Arg64 and Lys66) and side chain interactions (Thr67) in the IMPCH active site reorient the 4-carboxamide from the preferred conformer that binds to the AICAR Tfase active site to one that promotes intramolecular cyclization. Other backbone amides (Ile126 and Gly127) create an oxyanion hole that helps orient the formyl group for nucleophilic attack by the 4-carboxamide amine and then stabilize the anionic intermediate. Several other residues, including Lys66, Tyr104, Asp125, and Lys137', provide substrate specificity and likely enhance the catalytic rate through contributions to acid-base catalysis. |
==Disease== | ==Disease== | ||
| Line 11: | Line 10: | ||
==About this Structure== | ==About this Structure== | ||
| - | 1PKX 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 K and XMP as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | + | 1PKX 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=K:'>K</scene> and <scene name='pdbligand=XMP:'>XMP</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1PKX OCA]. |
==Reference== | ==Reference== | ||
| Line 17: | Line 16: | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Cheong, C | + | [[Category: Cheong, C G.]] |
| - | [[Category: Greasley, S | + | [[Category: Greasley, S E.]] |
| - | [[Category: Wilson, I | + | [[Category: Wilson, I A.]] |
| - | [[Category: Wolan, D | + | [[Category: Wolan, D W.]] |
[[Category: K]] | [[Category: K]] | ||
[[Category: XMP]] | [[Category: XMP]] | ||
| Line 29: | Line 28: | ||
[[Category: xanthosine monophosphate]] | [[Category: xanthosine monophosphate]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:29:53 2008'' |
Revision as of 12:29, 21 February 2008
|
Crystal Structure of human ATIC in complex with XMP
Contents |
Overview
Within de novo purine biosynthesis, the AICAR transformylase and IMP cyclohydrolase activities of the bifunctional enzyme ATIC convert the intermediate AICAR to the final product of the pathway, IMP. Identification of the AICAR transformylase active site and a proposed formyl transfer mechanism have already resulted from analysis of crystal structures of avian ATIC in complex with substrate and/or inhibitors. Herein, we focus on the IMPCH active site and the cyclohydrolase mechanism through comparison of crystal structures of XMP inhibitor complexes of human ATIC at 1.9 A resolution with the previously determined avian enzyme. This first human ATIC structure was also determined to ascertain whether any subtle structural differences, compared to the homologous avian enzyme, should be taken into account for structure-based inhibitor design. These structural comparisons, as well as comparative analyses with other IMP and XMP binding proteins, have enabled a catalytic mechanism to be formulated. The primary role of the IMPCH active site appears to be to induce a reconfiguration of the substrate FAICAR to a less energetically favorable, but more reactive, conformer. Backbone (Arg64 and Lys66) and side chain interactions (Thr67) in the IMPCH active site reorient the 4-carboxamide from the preferred conformer that binds to the AICAR Tfase active site to one that promotes intramolecular cyclization. Other backbone amides (Ile126 and Gly127) create an oxyanion hole that helps orient the formyl group for nucleophilic attack by the 4-carboxamide amine and then stabilize the anionic intermediate. Several other residues, including Lys66, Tyr104, Asp125, and Lys137', provide substrate specificity and likely enhance the catalytic rate through contributions to acid-base catalysis.
Disease
Known diseases associated with this structure: AICA-ribosiduria due to ATIC deficiency OMIM:[601731]
About this Structure
1PKX is a Single protein structure of sequence from Homo sapiens with and as ligands. Full crystallographic information is available from OCA.
Reference
Structural insights into the human and avian IMP cyclohydrolase mechanism via crystal structures with the bound XMP inhibitor., Wolan DW, Cheong CG, Greasley SE, Wilson IA, Biochemistry. 2004 Feb 10;43(5):1171-83. PMID:14756553
Page seeded by OCA on Thu Feb 21 14:29:53 2008
