1pvn
From Proteopedia
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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 K, MZP and TRS as ligands. This structure superseeds 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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