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==Pantothenate synthetase in complex with 6-methoxy-1-benzofuran-3-yl acetic acid== | |||
<StructureSection load='4ddh' size='340' side='right' caption='[[4ddh]], [[Resolution|resolution]] 2.07Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4ddh]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DDH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DDH 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=EOH:ETHANOL'>EOH</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MS0:(6-METHOXY-1-BENZOFURAN-3-YL)ACETIC+ACID'>MS0</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ddk|4ddk]], [[4ddm|4ddm]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MT3707, MTCY07H7B.20, panC, Rv3602c ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 Mycobacterium tuberculosis])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Pantoate--beta-alanine_ligase Pantoate--beta-alanine ligase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.3.2.1 6.3.2.1] </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=4ddh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ddh OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ddh RCSB], [http://www.ebi.ac.uk/pdbsum/4ddh PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
In fragment-based drug discovery, the weak affinities exhibited by fragments pose significant challenges for screening. Biophysical techniques are used to address this challenge, but there is no clear consensus on which cascade of methods is best suited to identify fragment hits that ultimately translate into bound X-ray structures and provide bona fide starting points for synthesis. We have benchmarked an integrated biophysical approach for fragment screening and validation against Mycobacterium tuberculosis pantothenate synthetase. A primary screen of 1,250 fragments library was performed by thermal shift, followed by secondary screen using one-dimensional NMR spectroscopy (water ligand observed gradient spectroscopy and saturation transfer difference binding experiments) and ultimate hit validation by isothermal titration calorimetry and X-ray crystallography. Our multibiophysical approach identified three distinct binding sites for fragments and laid a solid foundation for successful structure-based elaboration into potent inhibitors. | |||
Integrated biophysical approach to fragment screening and validation for fragment-based lead discovery.,Silvestre HL, Blundell TL, Abell C, Ciulli A Proc Natl Acad Sci U S A. 2013 Jul 19. PMID:23872845<ref>PMID:23872845</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== | ==See Also== | ||
*[[Pantothenate synthetase|Pantothenate synthetase]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Mycobacterium tuberculosis]] | [[Category: Mycobacterium tuberculosis]] | ||
[[Category: Pantoate--beta-alanine ligase]] | [[Category: Pantoate--beta-alanine ligase]] | ||
[[Category: Silvestre, H L | [[Category: Silvestre, H L]] | ||
[[Category: Alpha beta/adenine nucleotide alpha hydrolase-like]] | [[Category: Alpha beta/adenine nucleotide alpha hydrolase-like]] | ||
[[Category: Fragment-based drug discovery]] | [[Category: Fragment-based drug discovery]] | ||
[[Category: Ligase-ligase inhibitor complex]] | [[Category: Ligase-ligase inhibitor complex]] | ||
[[Category: Pantoate and b-ala binding]] | [[Category: Pantoate and b-ala binding]] | ||
Revision as of 12:25, 21 December 2014
Pantothenate synthetase in complex with 6-methoxy-1-benzofuran-3-yl acetic acidPantothenate synthetase in complex with 6-methoxy-1-benzofuran-3-yl acetic acid
Structural highlights
Publication Abstract from PubMedIn fragment-based drug discovery, the weak affinities exhibited by fragments pose significant challenges for screening. Biophysical techniques are used to address this challenge, but there is no clear consensus on which cascade of methods is best suited to identify fragment hits that ultimately translate into bound X-ray structures and provide bona fide starting points for synthesis. We have benchmarked an integrated biophysical approach for fragment screening and validation against Mycobacterium tuberculosis pantothenate synthetase. A primary screen of 1,250 fragments library was performed by thermal shift, followed by secondary screen using one-dimensional NMR spectroscopy (water ligand observed gradient spectroscopy and saturation transfer difference binding experiments) and ultimate hit validation by isothermal titration calorimetry and X-ray crystallography. Our multibiophysical approach identified three distinct binding sites for fragments and laid a solid foundation for successful structure-based elaboration into potent inhibitors. Integrated biophysical approach to fragment screening and validation for fragment-based lead discovery.,Silvestre HL, Blundell TL, Abell C, Ciulli A Proc Natl Acad Sci U S A. 2013 Jul 19. PMID:23872845[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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