1pvn

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{{STRUCTURE_1pvn| PDB=1pvn | SCENE= }}
{{STRUCTURE_1pvn| PDB=1pvn | SCENE= }}
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'''The crystal structure of the complex between IMP dehydrogenase catalytic domain and a transition state analogue MZP'''
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===The crystal structure of the complex between IMP dehydrogenase catalytic domain and a transition state analogue MZP===
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==Overview==
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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.
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(as it appears on PubMed at http://www.pubmed.gov), where 12549902 is the PubMed ID number.
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{{ABSTRACT_PUBMED_12549902}}
==About this Structure==
==About this Structure==
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[[Category: Mizoribine 5'-monophosphate]]
[[Category: Mizoribine 5'-monophosphate]]
[[Category: Transition state analogue]]
[[Category: Transition state analogue]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 05:32:16 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 05:17:57 2008''

Revision as of 02:18, 29 July 2008

Image:1pvn.png

Template:STRUCTURE 1pvn

The crystal structure of the complex between IMP dehydrogenase catalytic domain and a transition state analogue MZP

Template:ABSTRACT PUBMED 12549902

About this Structure

1PVN is a Single protein structure of sequence from Tritrichomonas foetus. This structure supersedes the now removed PDB entry 1mwf. 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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