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| | ==Crystal Structure of the Catalytic Domain of the Inosine Monophosphate Dehydrogenase from Cryptosporidium parvum== | | ==Crystal Structure of the Catalytic Domain of the Inosine Monophosphate Dehydrogenase from Cryptosporidium parvum== |
| - | <StructureSection load='4ixh' size='340' side='right' caption='[[4ixh]], [[Resolution|resolution]] 2.10Å' scene=''> | + | <StructureSection load='4ixh' size='340' side='right'caption='[[4ixh]], [[Resolution|resolution]] 2.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4ixh]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Crypv Crypv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4IXH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4IXH FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4ixh]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Cryptosporidium_parvum Cryptosporidium parvum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4IXH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4IXH FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=IMP:INOSINIC+ACID'>IMP</scene>, <scene name='pdbligand=Q21:(2S)-2-(NAPHTHALEN-1-YLOXY)-N-[2-(PYRIDIN-4-YL)-1,3-BENZOXAZOL-5-YL]PROPANAMIDE'>Q21</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.105Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3ffs|3ffs]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=IMP:INOSINIC+ACID'>IMP</scene>, <scene name='pdbligand=Q21:(2S)-2-(NAPHTHALEN-1-YLOXY)-N-[2-(PYRIDIN-4-YL)-1,3-BENZOXAZOL-5-YL]PROPANAMIDE'>Q21</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">56k.02, cgd6_20 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5807 CRYPV])</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4ixh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ixh OCA], [https://pdbe.org/4ixh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ixh RCSB], [https://www.ebi.ac.uk/pdbsum/4ixh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ixh ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </span></td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ixh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ixh OCA], [http://pdbe.org/4ixh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ixh RCSB], [http://www.ebi.ac.uk/pdbsum/4ixh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ixh ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/IMDH_CRYPV IMDH_CRYPV]] Catalyzes the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate-limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of cell growth (By similarity).<ref>PMID:15269207</ref> | + | [https://www.uniprot.org/uniprot/IMDH_CRYPV IMDH_CRYPV] Catalyzes the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate-limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of cell growth (By similarity).<ref>PMID:15269207</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Inosine monophosphate dehydrogenase|Inosine monophosphate dehydrogenase]] | + | *[[Inosine monophosphate dehydrogenase 3D structures|Inosine monophosphate dehydrogenase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Crypv]] | + | [[Category: Cryptosporidium parvum]] |
| - | [[Category: IMP dehydrogenase]] | + | [[Category: Large Structures]] |
| - | [[Category: Anderson, W F]] | + | [[Category: Anderson WF]] |
| - | [[Category: Structural genomic]]
| + | [[Category: Gu M]] |
| - | [[Category: Gu, M]] | + | [[Category: Hedstrom L]] |
| - | [[Category: Hedstrom, L]] | + | [[Category: Joachimiak A]] |
| - | [[Category: Joachimiak, A]] | + | [[Category: Kavitha M]] |
| - | [[Category: Kavitha, M]] | + | [[Category: Kim Y]] |
| - | [[Category: Kim, Y]] | + | [[Category: Makowska-Grzyska M]] |
| - | [[Category: Makowska-Grzyska, M]] | + | |
| - | [[Category: Alpha-beta fold]]
| + | |
| - | [[Category: Csgid]]
| + | |
| - | [[Category: National institute of allergy and infectious disease]]
| + | |
| - | [[Category: Niaid]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Tim barrel]]
| + | |
| Structural highlights
Function
IMDH_CRYPV Catalyzes the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate-limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of cell growth (By similarity).[1]
Publication Abstract from PubMed
Cryptosporidium parvum is an enteric protozoan parasite that has emerged as a major cause of diarrhea, malnutrition, and gastroenteritis and poses a potential bioterrorism threat. C. parvum synthesizes guanine nucleotides from host adenosine in a streamlined pathway that relies on inosine 5'-monophosphate dehydrogenase (IMPDH). We have previously identified several parasite-selective C. parvum IMPDH (CpIMPDH) inhibitors by high-throughput screening. In this paper, we report the structure-activity relationship (SAR) for a series of benzoxazole derivatives with many compounds demonstrating CpIMPDH IC50 values in the nanomolar range and >500-fold selectivity over human IMPDH (hIMPDH). Unlike previously reported CpIMPDH inhibitors, these compounds are competitive inhibitors versus NAD(+). The SAR study reveals that pyridine and other small heteroaromatic substituents are required at the 2-position of the benzoxazole for potent inhibitory activity. In addition, several other SAR conclusions are highlighted with regard to the benzoxazole and the amide portion of the inhibitor, including preferred stereochemistry. An X-ray crystal structure of a representative E.IMP.inhibitor complex is also presented. Overall, the secondary amine derivative 15a demonstrated excellent CpIMPDH inhibitory activity (IC50 = 0.5 +/- 0.1 nM) and moderate stability (t1/2 = 44 min) in mouse liver microsomes. Compound 73, the racemic version of 15a, also displayed superb antiparasitic activity in a Toxoplasma gondii strain that relies on CpIMPDH (EC50 = 20 +/- 20 nM), and selectivity versus a wild-type T. gondii strain (200-fold). No toxicity was observed (LD50 > 50 muM) against a panel of four mammalian cells lines.
Optimization of Benzoxazole-Based Inhibitors of Cryptosporidium parvum Inosine 5'-Monophosphate Dehydrogenase.,Gorla SK, Kavitha M, Zhang M, Chin JE, Liu X, Striepen B, Makowska-Grzyska M, Kim Y, Joachimiak A, Hedstrom L, Cuny GD J Med Chem. 2013 May 23;56(10):4028-43. doi: 10.1021/jm400241j. Epub 2013 May 13. PMID:23668331[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Umejiego NN, Li C, Riera T, Hedstrom L, Striepen B. Cryptosporidium parvum IMP dehydrogenase: identification of functional, structural, and dynamic properties that can be exploited for drug design. J Biol Chem. 2004 Sep 24;279(39):40320-7. Epub 2004 Jul 21. PMID:15269207 doi:10.1074/jbc.M407121200
- ↑ Gorla SK, Kavitha M, Zhang M, Chin JE, Liu X, Striepen B, Makowska-Grzyska M, Kim Y, Joachimiak A, Hedstrom L, Cuny GD. Optimization of Benzoxazole-Based Inhibitors of Cryptosporidium parvum Inosine 5'-Monophosphate Dehydrogenase. J Med Chem. 2013 May 23;56(10):4028-43. doi: 10.1021/jm400241j. Epub 2013 May 13. PMID:23668331 doi:10.1021/jm400241j
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