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==Crystal structure of SAICAR Synthetase (PurC) from Mycobacterium abscessus in complex with inhibitor== | ==Crystal structure of SAICAR Synthetase (PurC) from Mycobacterium abscessus in complex with inhibitor== | ||
<StructureSection load='6yyd' size='340' side='right'caption='[[6yyd]]' scene=''> | <StructureSection load='6yyd' size='340' side='right'caption='[[6yyd]], [[Resolution|resolution]] 1.39Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6YYD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6YYD FirstGlance]. <br> | <table><tr><td colspan='2'>[[6yyd]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Myca9 Myca9]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6YYD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6YYD FirstGlance]. <br> | ||
</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=6yyd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yyd OCA], [https://pdbe.org/6yyd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6yyd RCSB], [https://www.ebi.ac.uk/pdbsum/6yyd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6yyd ProSAT]</span></td></tr> | </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=Q0H:4-azanyl-6-[1-[[3,4-bis(fluoranyl)phenyl]methyl]pyrazol-4-yl]pyrimidine-5-carbonitrile'>Q0H</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">purC, MAB_0689 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=561007 MYCA9])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Phosphoribosylaminoimidazolesuccinocarboxamide_synthase Phosphoribosylaminoimidazolesuccinocarboxamide synthase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.3.2.6 6.3.2.6] </span></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=6yyd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yyd OCA], [https://pdbe.org/6yyd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6yyd RCSB], [https://www.ebi.ac.uk/pdbsum/6yyd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6yyd ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Mycobacterium abscessus (Mab) has emerged as a challenging threat to individuals with cystic fibrosis. Infections caused by this pathogen are often impossible to treat due to the intrinsic antibiotic resistance leading to lung malfunction and eventually death. Therefore, there is an urgent need to develop new drugs against novel targets in Mab to overcome drug resistance and subsequent treatment failure. In this study, SAICAR synthetase (PurC) from Mab was identified as a promising target for novel antibiotics. An in-house fragment library screen and a high-throughput X-ray crystallographic screen of diverse fragment libraries were explored to provide crucial starting points for fragment elaboration. A series of compounds developed from fragment growing and merging strategies, guided by crystallographic information and careful hit-to-lead optimization, have achieved potent nanomolar binding affinity against the enzyme. Some compounds also show a promising inhibitory effect against Mab and Mtb. This work utilizes a fragment-based design and demonstrates for the first time the potential to develop inhibitors against PurC from Mab. | |||
Development of Inhibitors of SAICAR Synthetase (PurC) from Mycobacterium abscessus Using a Fragment-Based Approach.,Charoensutthivarakul S, Thomas SE, Curran A, Brown KP, Belardinelli JM, Whitehouse AJ, Acebron-Garcia-de-Eulate M, Sangan J, Gramani SG, Jackson M, Mendes V, Floto RA, Blundell TL, Coyne AG, Abell C ACS Infect Dis. 2022 Feb 11;8(2):296-309. doi: 10.1021/acsinfecdis.1c00432. Epub , 2022 Jan 17. PMID:35037462<ref>PMID:35037462</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6yyd" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Abell C]] | [[Category: Myca9]] | ||
[[Category: Blundell | [[Category: Phosphoribosylaminoimidazolesuccinocarboxamide synthase]] | ||
[[Category: Charoensutthivarakul S]] | [[Category: Abell, C]] | ||
[[Category: Coyne | [[Category: Blundell, T L]] | ||
[[Category: Thomas | [[Category: Charoensutthivarakul, S]] | ||
[[Category: Coyne, A G]] | |||
[[Category: Thomas, S E]] | |||
[[Category: Ligase]] | |||
[[Category: Phosphoribosylaminoimidazole-succinocarboxamide synthase]] | |||
[[Category: Purc]] | |||
[[Category: Purine biosynthesis]] | |||
[[Category: Saicar synthetase]] | |||
Revision as of 13:46, 16 February 2022
Crystal structure of SAICAR Synthetase (PurC) from Mycobacterium abscessus in complex with inhibitorCrystal structure of SAICAR Synthetase (PurC) from Mycobacterium abscessus in complex with inhibitor
Structural highlights
Publication Abstract from PubMedMycobacterium abscessus (Mab) has emerged as a challenging threat to individuals with cystic fibrosis. Infections caused by this pathogen are often impossible to treat due to the intrinsic antibiotic resistance leading to lung malfunction and eventually death. Therefore, there is an urgent need to develop new drugs against novel targets in Mab to overcome drug resistance and subsequent treatment failure. In this study, SAICAR synthetase (PurC) from Mab was identified as a promising target for novel antibiotics. An in-house fragment library screen and a high-throughput X-ray crystallographic screen of diverse fragment libraries were explored to provide crucial starting points for fragment elaboration. A series of compounds developed from fragment growing and merging strategies, guided by crystallographic information and careful hit-to-lead optimization, have achieved potent nanomolar binding affinity against the enzyme. Some compounds also show a promising inhibitory effect against Mab and Mtb. This work utilizes a fragment-based design and demonstrates for the first time the potential to develop inhibitors against PurC from Mab. Development of Inhibitors of SAICAR Synthetase (PurC) from Mycobacterium abscessus Using a Fragment-Based Approach.,Charoensutthivarakul S, Thomas SE, Curran A, Brown KP, Belardinelli JM, Whitehouse AJ, Acebron-Garcia-de-Eulate M, Sangan J, Gramani SG, Jackson M, Mendes V, Floto RA, Blundell TL, Coyne AG, Abell C ACS Infect Dis. 2022 Feb 11;8(2):296-309. doi: 10.1021/acsinfecdis.1c00432. Epub , 2022 Jan 17. PMID:35037462[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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