5ou2: Difference between revisions
New page: '''Unreleased structure''' The entry 5ou2 is ON HOLD Authors: Description: Category: Unreleased Structures |
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==M. thermoresistible IMPDH in complex with IMP and Compound 2 (NMR744)== | |||
<StructureSection load='5ou2' size='340' side='right'caption='[[5ou2]], [[Resolution|resolution]] 1.45Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5ou2]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycolicibacterium_thermoresistibile_ATCC_19527 Mycolicibacterium thermoresistibile ATCC 19527]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OU2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5OU2 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.45Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=36Y:4-(4-BROMOPHENYL)-1H-IMIDAZOLE'>36Y</scene>, <scene name='pdbligand=IMP:INOSINIC+ACID'>IMP</scene></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=5ou2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ou2 OCA], [https://pdbe.org/5ou2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ou2 RCSB], [https://www.ebi.ac.uk/pdbsum/5ou2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ou2 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/G7CNL4_MYCT3 G7CNL4_MYCT3] 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.[HAMAP-Rule:MF_01964] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Tuberculosis (TB) remains a major cause of mortality worldwide, and improved treatments are needed to combat emergence of drug resistance. Inosine 5'-monophosphate dehydrogenase (IMPDH), a crucial enzyme required for de novo synthesis of guanine nucleotides, is an attractive TB drug target. Herein, we describe the identification of potent IMPDH inhibitors using fragment-based screening and structure-based design techniques. Screening of a fragment library for Mycobacterium thermoresistible ( Mth) IMPDH DeltaCBS inhibitors identified a low affinity phenylimidazole derivative. X-ray crystallography of the Mth IMPDH DeltaCBS-IMP-inhibitor complex revealed that two molecules of the fragment were bound in the NAD binding pocket of IMPDH. Linking the two molecules of the fragment afforded compounds with more than 1000-fold improvement in IMPDH affinity over the initial fragment hit. | |||
Fragment-Based Approach to Targeting Inosine-5'-monophosphate Dehydrogenase (IMPDH) from Mycobacterium tuberculosis.,Trapero A, Pacitto A, Singh V, Sabbah M, Coyne AG, Mizrahi V, Blundell TL, Ascher DB, Abell C J Med Chem. 2018 Mar 23. doi: 10.1021/acs.jmedchem.7b01622. PMID:29547284<ref>PMID:29547284</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 5ou2" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Inosine monophosphate dehydrogenase 3D structures|Inosine monophosphate dehydrogenase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Mycolicibacterium thermoresistibile ATCC 19527]] | |||
[[Category: Ascher DB]] | |||
[[Category: Blundell TL]] | |||
[[Category: Pacitto A]] | |||
Latest revision as of 04:24, 28 December 2023
M. thermoresistible IMPDH in complex with IMP and Compound 2 (NMR744)M. thermoresistible IMPDH in complex with IMP and Compound 2 (NMR744)
Structural highlights
FunctionG7CNL4_MYCT3 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.[HAMAP-Rule:MF_01964] Publication Abstract from PubMedTuberculosis (TB) remains a major cause of mortality worldwide, and improved treatments are needed to combat emergence of drug resistance. Inosine 5'-monophosphate dehydrogenase (IMPDH), a crucial enzyme required for de novo synthesis of guanine nucleotides, is an attractive TB drug target. Herein, we describe the identification of potent IMPDH inhibitors using fragment-based screening and structure-based design techniques. Screening of a fragment library for Mycobacterium thermoresistible ( Mth) IMPDH DeltaCBS inhibitors identified a low affinity phenylimidazole derivative. X-ray crystallography of the Mth IMPDH DeltaCBS-IMP-inhibitor complex revealed that two molecules of the fragment were bound in the NAD binding pocket of IMPDH. Linking the two molecules of the fragment afforded compounds with more than 1000-fold improvement in IMPDH affinity over the initial fragment hit. Fragment-Based Approach to Targeting Inosine-5'-monophosphate Dehydrogenase (IMPDH) from Mycobacterium tuberculosis.,Trapero A, Pacitto A, Singh V, Sabbah M, Coyne AG, Mizrahi V, Blundell TL, Ascher DB, Abell C J Med Chem. 2018 Mar 23. doi: 10.1021/acs.jmedchem.7b01622. PMID:29547284[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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