4w1v: Difference between revisions
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==Crystal structure of 7,8-diaminopelargonic acid synthase (BioA) from Mycobacterium tuberculosis, complexed with a thiazole inhibitor== | |||
<StructureSection load='4w1v' size='340' side='right'caption='[[4w1v]], [[Resolution|resolution]] 2.24Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4w1v]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_CDC1551 Mycobacterium tuberculosis CDC1551]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4W1V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4W1V 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]] 2.24Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3GS:DIMETHYL+(2R)-5-(3-FLUOROPHENYL)-1H-PYRROLO[1,2-C][1,3]THIAZOLE-6,7-DICARBOXYLATE+2-OXIDE'>3GS</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</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=4w1v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4w1v OCA], [https://pdbe.org/4w1v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4w1v RCSB], [https://www.ebi.ac.uk/pdbsum/4w1v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4w1v ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/BIOA_MYCTO BIOA_MYCTO] Catalyzes the transfer of the alpha-amino group from S-adenosyl-L-methionine (SAM) to 7-keto-8-aminopelargonic acid (KAPA) to form 7,8-diaminopelargonic acid (DAPA). It is the only animotransferase known to utilize SAM as an amino donor (By similarity). | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Biotin biosynthesis is essential for survival and persistence of Mycobacterium tuberculosis (Mtb) in vivo. The aminotransferase BioA, which catalyzes the antepenultimate step in the biotin pathway, has been established as a promising target due to its vulnerability to chemical inhibition. We performed high-throughput screening (HTS) employing a fluorescence displacement assay and identified a diverse set of potent inhibitors including many diversity-oriented synthesis (DOS) scaffolds. To efficiently select only hits targeting biotin biosynthesis, we then deployed a whole-cell counterscreen in biotin-free and biotin-containing medium against wild-type Mtb and in parallel with isogenic bioA Mtb strains that possess differential levels of BioA expression. This counterscreen proved crucial to filter out compounds whose whole-cell activity was off target as well as identify hits with weak, but measurable whole-cell activity in BioA-depleted strains. Several of the most promising hits were cocrystallized with BioA to provide a framework for future structure-based drug design efforts. | |||
Target-Based Identification of Whole-Cell Active Inhibitors of Biotin Biosynthesis in Mycobacterium tuberculosis.,Park SW, Casalena DE, Wilson DJ, Dai R, Nag PP, Liu F, Boyce JP, Bittker JA, Schreiber SL, Finzel BC, Schnappinger D, Aldrich CC Chem Biol. 2015 Jan 22;22(1):76-86. doi: 10.1016/j.chembiol.2014.11.012. Epub, 2014 Dec 31. PMID:25556942<ref>PMID:25556942</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4w1v" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Aminotransferase 3D structures|Aminotransferase 3D structures]] | |||
*[[7%2C8-diaminopelargonic acid synthase 3D structures|7%2C8-diaminopelargonic acid synthase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Mycobacterium tuberculosis CDC1551]] | |||
[[Category: Dai R]] | |||
[[Category: Finzel BC]] | |||
Latest revision as of 03:50, 28 December 2023
Crystal structure of 7,8-diaminopelargonic acid synthase (BioA) from Mycobacterium tuberculosis, complexed with a thiazole inhibitorCrystal structure of 7,8-diaminopelargonic acid synthase (BioA) from Mycobacterium tuberculosis, complexed with a thiazole inhibitor
Structural highlights
FunctionBIOA_MYCTO Catalyzes the transfer of the alpha-amino group from S-adenosyl-L-methionine (SAM) to 7-keto-8-aminopelargonic acid (KAPA) to form 7,8-diaminopelargonic acid (DAPA). It is the only animotransferase known to utilize SAM as an amino donor (By similarity). Publication Abstract from PubMedBiotin biosynthesis is essential for survival and persistence of Mycobacterium tuberculosis (Mtb) in vivo. The aminotransferase BioA, which catalyzes the antepenultimate step in the biotin pathway, has been established as a promising target due to its vulnerability to chemical inhibition. We performed high-throughput screening (HTS) employing a fluorescence displacement assay and identified a diverse set of potent inhibitors including many diversity-oriented synthesis (DOS) scaffolds. To efficiently select only hits targeting biotin biosynthesis, we then deployed a whole-cell counterscreen in biotin-free and biotin-containing medium against wild-type Mtb and in parallel with isogenic bioA Mtb strains that possess differential levels of BioA expression. This counterscreen proved crucial to filter out compounds whose whole-cell activity was off target as well as identify hits with weak, but measurable whole-cell activity in BioA-depleted strains. Several of the most promising hits were cocrystallized with BioA to provide a framework for future structure-based drug design efforts. Target-Based Identification of Whole-Cell Active Inhibitors of Biotin Biosynthesis in Mycobacterium tuberculosis.,Park SW, Casalena DE, Wilson DJ, Dai R, Nag PP, Liu F, Boyce JP, Bittker JA, Schreiber SL, Finzel BC, Schnappinger D, Aldrich CC Chem Biol. 2015 Jan 22;22(1):76-86. doi: 10.1016/j.chembiol.2014.11.012. Epub, 2014 Dec 31. PMID:25556942[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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