1PVN

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

Replaces:  1MWF

Summary for 1PVN

• Entry DOI: 10.2210/pdb1pvn/pdb
• Related: 1LRT
• Descriptor: Inosine-5'-monophosphate dehydrogenase, POTASSIUM ION, 4-CARBAMOYL-1-BETA-D-RIBOFURANOSYL-IMIDAZOLIUM-5-OLATE-5'-PHOSPHATE, ... (5 entities in total)
• Functional Keywords: transition state analogue, imp dehydrogenase, mizoribine 5'-monophosphate, distal flap, general base, drug selectivity, oxidoreductase
• Biological source: Tritrichomonas foetus; More
• Cellular location: Cytoplasm : P50097
• Total number of polymer chains: 4
• Total formula weight: 167246.02

Authors

Gan, L.,Seyedsayamdost, M.,Shuto, S.,Matsuda, A.,Petsko, G.A.,Hedstrom, L. (deposition date: 2003-06-27, release date: 2003-07-22, Last modification date: 2023-08-16)

Primary citation

Gan, L.,Seyedsayamdost, M.,Shuto, S.,Matsuda, A.,Petsko, G.A.,Hedstrom, L.
The Immunosuppressive Agent Mizoribine Monophosphate Forms a Transition State Analogue Complex with Inosine Monophosphate Dehydrogenase
Biochemistry, 42:857-863, 2003

PubMed Abstract: 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.

PubMed: 12549902
DOI: 10.1021/bi0271401

Experimental method

X-RAY DIFFRACTION (2 Å)