4xjo: Difference between revisions
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4xjo]] 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=4XJO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4XJO FirstGlance]. <br> | <table><tr><td colspan='2'>[[4xjo]] 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=4XJO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4XJO FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=41O:5-[4-(3-CHLOROBENZOYL)PIPERAZIN-1-YL]-1H-INDEN-1-ONE'>41O</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.5Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=41O:5-[4-(3-CHLOROBENZOYL)PIPERAZIN-1-YL]-1H-INDEN-1-ONE'>41O</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</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=4xjo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xjo OCA], [https://pdbe.org/4xjo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xjo RCSB], [https://www.ebi.ac.uk/pdbsum/4xjo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xjo ProSAT]</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=4xjo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xjo OCA], [https://pdbe.org/4xjo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xjo RCSB], [https://www.ebi.ac.uk/pdbsum/4xjo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xjo ProSAT]</span></td></tr> | ||
</table> | </table> | ||
Latest revision as of 10:46, 27 September 2023
Crystal structure of 7,8-diaminopelargonic acid synthase (BioA) from Mycobacterium tuberculosis, complexed with an inhibitor optimized from HTS leadCrystal structure of 7,8-diaminopelargonic acid synthase (BioA) from Mycobacterium tuberculosis, complexed with an inhibitor optimized from HTS lead
Structural highlights
FunctionBIOA_MYCTU Catalyzes the reversible 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. Can also use sinefungin as substrate.[1] Publication Abstract from PubMedThe pyridoxal 5'-phosphate (PLP)-dependent transaminase BioA catalyzes the second step in the biosynthesis of biotin in Mycobacterium tuberculosis (Mtb) and is an essential enzyme for bacterial survival and persistence in vivo. A promising BioA inhibitor 6 containing an N-aryl, N'-benzoylpiperazine scaffold was previously identified by target-based whole-cell screening. Here, we explore the structure-activity relationships (SAR) through the design, synthesis, and biological evaluation of a systematic series of analogues of the original hit using a structure-based drug design strategy, which was enabled by cocrystallization of several analogues with BioA. To confirm target engagement and discern analogues with off-target activity, each compound was evaluated against wild-type (WT) Mtb in biotin-free and -containing medium as well as BioA under- and overexpressing Mtb strains. Conformationally constrained derivative 36 emerged as the most potent analogue with a KD of 76 nM against BioA and a minimum inhibitory concentration of 1.7 muM (0.6 mug/mL) against Mtb in biotin-free medium. Structure-Based Optimization of Pyridoxal 5'-Phosphate-Dependent Transaminase Enzyme (BioA) Inhibitors that Target Biotin Biosynthesis in Mycobacterium tuberculosis.,Liu F, Dawadi S, Maize KM, Dai R, Park SW, Schnappinger D, Finzel BC, Aldrich CC J Med Chem. 2017 Jul 13;60(13):5507-5520. doi: 10.1021/acs.jmedchem.7b00189. Epub, 2017 Jun 22. PMID:28594172[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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