1pvn: Difference between revisions
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New page: left|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'' | ||
