6yya: Difference between revisions
New page: '''Unreleased structure''' The entry 6yya is ON HOLD until Paper Publication Authors: Thomas, S.E., Charoensutthivarakul, S., Coyne, A.G., Abell, C., Blundell, T.L. Description: Crysta... |
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==Crystal structure of SAICAR Synthetase (PurC) from Mycobacterium abscessus in complex with inhibitor== | |||
<StructureSection load='6yya' size='340' side='right'caption='[[6yya]], [[Resolution|resolution]] 1.41Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6yya]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacteroides_abscessus_ATCC_19977 Mycobacteroides abscessus ATCC 19977]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6YYA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6YYA 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]] 1.41Å</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=PZK:4-azanyl-6-[1-[(3-fluorophenyl)methyl]pyrazol-4-yl]pyrimidine-5-carbonitrile'>PZK</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6yya FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yya OCA], [https://pdbe.org/6yya PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6yya RCSB], [https://www.ebi.ac.uk/pdbsum/6yya PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6yya ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/PUR7_MYCA9 PUR7_MYCA9] | |||
<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> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6yya" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: | ==See Also== | ||
[[Category: Charoensutthivarakul | *[[SAICAR synthetase|SAICAR synthetase]] | ||
[[Category: Coyne | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Mycobacteroides abscessus ATCC 19977]] | |||
[[Category: Abell C]] | |||
[[Category: Blundell TL]] | |||
[[Category: Charoensutthivarakul S]] | |||
[[Category: Coyne AG]] | |||
[[Category: Thomas SE]] | |||
Latest revision as of 16:38, 24 January 2024
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
FunctionPublication 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. See AlsoReferences
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