1pvn
From Proteopedia
(New page: 200px<br /><applet load="1pvn" size="450" color="white" frame="true" align="right" spinBox="true" caption="1pvn, resolution 2.00Å" /> '''The crystal structur...) |
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| - | [[Image:1pvn.jpg|left|200px]]<br /><applet load="1pvn" size=" | + | [[Image:1pvn.jpg|left|200px]]<br /><applet load="1pvn" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1pvn, resolution 2.00Å" /> | caption="1pvn, resolution 2.00Å" /> | ||
'''The crystal structure of the complex between IMP dehydrogenase catalytic domain and a transition state analogue MZP'''<br /> | '''The crystal structure of the complex between IMP dehydrogenase catalytic domain and a transition state analogue MZP'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Mizoribine monophosphate (MZP) is the active metabolite of the | + | Mizoribine monophosphate (MZP) is the active metabolite of the immunosuppressive agent mizoribine and a potent inhibitor of IMP dehydrogenase (IMPDH). This enzyme catalyzes the oxidation of IMP to XMP with the concomitant reduction of NAD via a covalent intermediate at Cys319 (E-XMP). Surprisingly, mutational analysis indicates that MZP is a transition state analogue although its structure does not resemble that of the expected transition state. Here we report the X-ray crystal structure of the E.MZP complex at 2.0 A resolution that reveals a transition state-like structure and solves the mechanistic puzzle of the IMPDH reaction. The protein assumes a new conformation where a flap folds into the NAD site and MZP, Cys319, and a water molecule are arranged in a geometry resembling the transition state. The water appears to be activated by interactions with a conserved Arg418-Tyr419 dyad. Mutagenesis experiments confirm that this new closed conformation is required for the hydrolysis of E-XMP, but not for the reduction of NAD. The closed conformation provides a structural explanation for the differences in drug selectivity and catalytic efficiency of IMPDH isozymes. |
==About this Structure== | ==About this Structure== | ||
| - | 1PVN is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Tritrichomonas_foetus Tritrichomonas foetus] with K, MZP and TRS as [http://en.wikipedia.org/wiki/ligands ligands]. This structure | + | 1PVN is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Tritrichomonas_foetus Tritrichomonas foetus] with <scene name='pdbligand=K:'>K</scene>, <scene name='pdbligand=MZP:'>MZP</scene> and <scene name='pdbligand=TRS:'>TRS</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. This structure supersedes the now removed PDB entry 1MWF. Active as [http://en.wikipedia.org/wiki/IMP_dehydrogenase IMP dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.205 1.1.1.205] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1PVN OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Hedstrom, L.]] | [[Category: Hedstrom, L.]] | ||
[[Category: Matsuda, A.]] | [[Category: Matsuda, A.]] | ||
| - | [[Category: Petsko, G | + | [[Category: Petsko, G A.]] |
[[Category: Seyedsayamdost, M.]] | [[Category: Seyedsayamdost, M.]] | ||
[[Category: Shuto, S.]] | [[Category: Shuto, S.]] | ||
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[[Category: transition state analogue]] | [[Category: transition state analogue]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:32:58 2008'' |
Revision as of 12:33, 21 February 2008
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The crystal structure of the complex between IMP dehydrogenase catalytic domain and a transition state analogue MZP
Overview
Mizoribine monophosphate (MZP) is the active metabolite of the immunosuppressive agent mizoribine and a potent inhibitor of IMP dehydrogenase (IMPDH). This enzyme catalyzes the oxidation of IMP to XMP with the concomitant reduction of NAD via a covalent intermediate at Cys319 (E-XMP). Surprisingly, mutational analysis indicates that MZP is a transition state analogue although its structure does not resemble that of the expected transition state. Here we report the X-ray crystal structure of the E.MZP complex at 2.0 A resolution that reveals a transition state-like structure and solves the mechanistic puzzle of the IMPDH reaction. The protein assumes a new conformation where a flap folds into the NAD site and MZP, Cys319, and a water molecule are arranged in a geometry resembling the transition state. The water appears to be activated by interactions with a conserved Arg418-Tyr419 dyad. Mutagenesis experiments confirm that this new closed conformation is required for the hydrolysis of E-XMP, but not for the reduction of NAD. The closed conformation provides a structural explanation for the differences in drug selectivity and catalytic efficiency of IMPDH isozymes.
About this Structure
1PVN is a Single protein structure of sequence from Tritrichomonas foetus with , and as ligands. This structure supersedes the now removed PDB entry 1MWF. Active as IMP dehydrogenase, with EC number 1.1.1.205 Full crystallographic information is available from OCA.
Reference
The immunosuppressive agent mizoribine monophosphate forms a transition state analogue complex with inosine monophosphate dehydrogenase., Gan L, Seyedsayamdost MR, Shuto S, Matsuda A, Petsko GA, Hedstrom L, Biochemistry. 2003 Feb 4;42(4):857-63. PMID:12549902
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