3le8: Difference between revisions
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== | ==Crystal Structure of Mycobacterium Tuberculosis Pantothenate Synthetase at 1.70 Angstrom resolution in complex with 2-(2-((benzofuran-2-carboxamido)methyl)-5-methoxy-1H-indol-1-yl)acetic acid== | ||
[[http://www.uniprot.org/uniprot/PANC_MYCTU PANC_MYCTU | <StructureSection load='3le8' size='340' side='right'caption='[[3le8]], [[Resolution|resolution]] 1.70Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3le8]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3LE8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3LE8 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]] 1.7Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2B5:2-(2-((BENZOFURAN-2-CARBOXAMIDO)METHYL)-5-METHOXY-1H-INDOL-1-YL)ACETIC+ACID'>2B5</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=EOH:ETHANOL'>EOH</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=3le8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3le8 OCA], [https://pdbe.org/3le8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3le8 RCSB], [https://www.ebi.ac.uk/pdbsum/3le8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3le8 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/PANC_MYCTU PANC_MYCTU] Catalyzes the condensation of pantoate with beta-alanine in an ATP-dependent reaction via a pantoyl-adenylate intermediate.<ref>PMID:11669627</ref> | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/le/3le8_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3le8 ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Fragment-based methods are a new and emerging approach for the discovery of protein binders that are potential new therapeutic agents. Several ways of utilizing structural information to guide the inhibitor assembly have been explored to date. One of the approaches, application of interligand Overhauser effect (ILOE) observations, is of particular interest, as it does not require the availability of a three-dimensional protein structure and is an NMR-based method that can be applied to targets that cannot be observed directly because of their size. Fragments, as small and often hydrophobic molecules, suffer from problems including compound aggregation in an aqueous environment and nonspecific binding contributions, especially when screened at higher concentrations suitable for ILOE observations. Here we report how this problem can be overcome by applying a step-by-step iterative procedure that includes the application of optimized probe molecules with known binding modes to elucidate the unknown binding modes of fragments. An enzyme substrate with well-characterized binding was used as a starting point, and the relative binding modes of modified fragments derived from ILOE observations were used to guide the fragment linking, leading to a potent inhibitor of our model system, Mycobacterium tuberculosis pantothenate synthetase, a potential drug target. We have supported our NMR data with crystal structures, thus establishing the guidelines for optimizing the ILOE observations. This model study should expand the application of the technique in drug discovery. | |||
Optimization of the interligand overhauser effect for fragment linking: application to inhibitor discovery against Mycobacterium tuberculosis pantothenate synthetase.,Sledz P, Silvestre HL, Hung AW, Ciulli A, Blundell TL, Abell C J Am Chem Soc. 2010 Apr 7;132(13):4544-5. PMID:20232910<ref>PMID:20232910</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3le8" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[Pantothenate synthetase|Pantothenate synthetase]] | *[[Pantothenate synthetase|Pantothenate synthetase]] | ||
== References == | |||
== | <references/> | ||
__TOC__ | |||
[[Category: | </StructureSection> | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Abell | [[Category: Mycobacterium tuberculosis H37Rv]] | ||
[[Category: Blundell | [[Category: Abell C]] | ||
[[Category: Ciulli | [[Category: Blundell TL]] | ||
[[Category: Hung | [[Category: Ciulli A]] | ||
[[Category: Silvestre | [[Category: Hung AW]] | ||
[[Category: Sledz | [[Category: Silvestre HL]] | ||
[[Category: Sledz P]] | |||
Latest revision as of 11:35, 6 September 2023
Crystal Structure of Mycobacterium Tuberculosis Pantothenate Synthetase at 1.70 Angstrom resolution in complex with 2-(2-((benzofuran-2-carboxamido)methyl)-5-methoxy-1H-indol-1-yl)acetic acidCrystal Structure of Mycobacterium Tuberculosis Pantothenate Synthetase at 1.70 Angstrom resolution in complex with 2-(2-((benzofuran-2-carboxamido)methyl)-5-methoxy-1H-indol-1-yl)acetic acid
Structural highlights
FunctionPANC_MYCTU Catalyzes the condensation of pantoate with beta-alanine in an ATP-dependent reaction via a pantoyl-adenylate intermediate.[1] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedFragment-based methods are a new and emerging approach for the discovery of protein binders that are potential new therapeutic agents. Several ways of utilizing structural information to guide the inhibitor assembly have been explored to date. One of the approaches, application of interligand Overhauser effect (ILOE) observations, is of particular interest, as it does not require the availability of a three-dimensional protein structure and is an NMR-based method that can be applied to targets that cannot be observed directly because of their size. Fragments, as small and often hydrophobic molecules, suffer from problems including compound aggregation in an aqueous environment and nonspecific binding contributions, especially when screened at higher concentrations suitable for ILOE observations. Here we report how this problem can be overcome by applying a step-by-step iterative procedure that includes the application of optimized probe molecules with known binding modes to elucidate the unknown binding modes of fragments. An enzyme substrate with well-characterized binding was used as a starting point, and the relative binding modes of modified fragments derived from ILOE observations were used to guide the fragment linking, leading to a potent inhibitor of our model system, Mycobacterium tuberculosis pantothenate synthetase, a potential drug target. We have supported our NMR data with crystal structures, thus establishing the guidelines for optimizing the ILOE observations. This model study should expand the application of the technique in drug discovery. Optimization of the interligand overhauser effect for fragment linking: application to inhibitor discovery against Mycobacterium tuberculosis pantothenate synthetase.,Sledz P, Silvestre HL, Hung AW, Ciulli A, Blundell TL, Abell C J Am Chem Soc. 2010 Apr 7;132(13):4544-5. PMID:20232910[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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