4xtw: Difference between revisions

Latest revision as of 07:49, 27 September 2023

Mycobacterium tuberculosis biotin ligase complexed with bisubstrate inhibitor 46 with azide in place of 2'OH

Structural highlights

4xtw is a 2 chain structure with sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.3001447Å
Ligands:	44M, EDO
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

BIRA_MYCTU Catalyzes the transfer of biotin onto a conserved lysine residue of the biotin carboxyl carrier protein (BCCP) domain of acetyl-CoA carboxylase and converts it to active holo-BCCP (PubMed:18509457, PubMed:24723382). Forms an acyl-adenylate intermediate (PubMed:18509457, PubMed:24723382). Cannot use GTP or desthiobiotin (PubMed:18509457).^[1] ^[2]

Publication Abstract from PubMed

Mycobacterium tuberculosis (Mtb) responsible for both latent and symptomatic tuberculosis (TB) remains the second leading cause of mortality among infectious diseases worldwide. Mycobacterial biotin protein ligase (MtBPL) is an essential enzyme in Mtb and regulates lipid metabolism through the post-translational biotinylation of acyl coenzyme A carboxylases. We report the synthesis and evaluation of a systematic series of potent nucleoside-based inhibitors of MtBPL that contain modifications to the ribofuranosyl ring of the nucleoside. All compounds were characterized by isothermal titration calorimetry (ITC) and shown to bind potently with KD's below 2 nM. Additionally, we obtained high-resolution co-crystal structures for a majority of the compounds. Despite fairly uniform biochemical potency, the whole-cell Mtb activity varied greatly with minimum inhibitory concentrations (MIC) ranging from 0.78 to >100 microM. Cellular accumulation studies in Mtb showed a nearly 10-fold enhanced accumulation of a C-2'-alpha analog over the corresponding C-2'-beta analog, consistent with their differential whole-cell activity.

Targeting Mycobacterium tuberculosis Biotin Protein Ligase (MtBPL) with Nucleoside-Based Bisubstrate Adenylation Inhibitors.,Bockman MR, Kalinda AS, Petrelli R, De la Mora-Rey T, Tiwari D, Liu F, Dawadi S, Nandakumar M, Rhee KY, Schnappinger D, Finzel BC, Aldrich CC J Med Chem. 2015 Aug 24. PMID:26299766^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Purushothaman S, Gupta G, Srivastava R, Ramu VG, Surolia A. Ligand specificity of group I biotin protein ligase of Mycobacterium tuberculosis. PLoS One. 2008 May 28;3(5):e2320. doi: 10.1371/journal.pone.0002320. PMID:18509457 doi:https://dx.doi.org/10.1371/journal.pone.0002320
↑ Ma Q, Akhter Y, Wilmanns M, Ehebauer MT. Active site conformational changes upon reaction intermediate biotinyl-5'-AMP binding in biotin protein ligase from Mycobacterium tuberculosis. Protein Sci. 2014 Apr 9. doi: 10.1002/pro.2475. PMID:24723382 doi:https://dx.doi.org/10.1002/pro.2475
↑ Bockman MR, Kalinda AS, Petrelli R, De la Mora-Rey T, Tiwari D, Liu F, Dawadi S, Nandakumar M, Rhee KY, Schnappinger D, Finzel BC, Aldrich CC. Targeting Mycobacterium tuberculosis Biotin Protein Ligase (MtBPL) with Nucleoside-Based Bisubstrate Adenylation Inhibitors. J Med Chem. 2015 Aug 24. PMID:26299766 doi:https://dx.doi.org/10.1021/acs.jmedchem.5b00719

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Purushothaman S, Gupta G, Srivastava R, Ramu VG, Surolia A. Ligand specificity of group I biotin protein ligase of Mycobacterium tuberculosis. PLoS One. 2008 May 28;3(5):e2320. doi: 10.1371/journal.pone.0002320. PMID:18509457 doi:https://dx.doi.org/10.1371/journal.pone.0002320

[2] Ma Q, Akhter Y, Wilmanns M, Ehebauer MT. Active site conformational changes upon reaction intermediate biotinyl-5'-AMP binding in biotin protein ligase from Mycobacterium tuberculosis. Protein Sci. 2014 Apr 9. doi: 10.1002/pro.2475. PMID:24723382 doi:https://dx.doi.org/10.1002/pro.2475

[3] Bockman MR, Kalinda AS, Petrelli R, De la Mora-Rey T, Tiwari D, Liu F, Dawadi S, Nandakumar M, Rhee KY, Schnappinger D, Finzel BC, Aldrich CC. Targeting Mycobacterium tuberculosis Biotin Protein Ligase (MtBPL) with Nucleoside-Based Bisubstrate Adenylation Inhibitors. J Med Chem. 2015 Aug 24. PMID:26299766 doi:https://dx.doi.org/10.1021/acs.jmedchem.5b00719

[1]

[2]

[3]

@@ Line 3: / Line 3: @@
 <StructureSection load='4xtw' size='340' side='right'caption='[[4xtw]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4xtw]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4XTW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4XTW FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4xtw]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4XTW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4XTW FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=44M:2-AZIDO-2,5-DIDEOXY-5-[({5-[(3AS,4S,6AR)-2-OXOHEXAHYDRO-1H-THIENO[3,4-D]IMIDAZOL-4-YL]PENTANOYL}SULFAMOYL)AMINO]ADENOSINE'>44M</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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]] 2.3001447&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4xtu|4xtu]], [[4xtv|4xtv]], [[4xtx|4xtx]], [[4xty|4xty]], [[4xtz|4xtz]], [[4xu0|4xu0]], [[4xu1|4xu1]], [[4xu2|4xu2]], [[4xu3|4xu3]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=44M:2-AZIDO-2,5-DIDEOXY-5-[({5-[(3AS,4S,6AR)-2-OXOHEXAHYDRO-1H-THIENO[3,4-D]IMIDAZOL-4-YL]PENTANOYL}SULFAMOYL)AMINO]ADENOSINE'>44M</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">birA, CH81_03124, CH82_03406, CH84_03412, CH85_03111, CH87_01691, CH88_02592, CO60_3782, ER17_17395, FF22_02902, FI98_01129, IQ38_01820, IQ39_01720, IQ40_01775, IQ41_01700, IQ42_01770, IQ43_01710, IQ44_01750, IQ45_01765, IQ46_01705, IQ47_01735, IQ48_01770, IU12_01860, IU13_01785, IU14_01730, IU16_01770, IU17_01745, IU18_01730, IU19_01775, IU20_01750, IU22_01755, IU23_01750, IU24_01735, IZ84_17515, JE53_17495, LJ70_17695, T209_01770 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 "Bacillus tuberculosis" (Zopf 1883) Klein 1884])</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=4xtw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xtw OCA], [https://pdbe.org/4xtw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xtw RCSB], [https://www.ebi.ac.uk/pdbsum/4xtw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xtw ProSAT]</span></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Biotin--[acetyl-CoA-carboxylase]_ligase Biotin--[acetyl-CoA-carboxylase] ligase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.3.4.15 6.3.4.15] </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=4xtw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xtw OCA], [http://pdbe.org/4xtw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4xtw RCSB], [http://www.ebi.ac.uk/pdbsum/4xtw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4xtw ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/BIRA_MYCTU BIRA_MYCTU] Catalyzes the transfer of biotin onto a conserved lysine residue of the biotin carboxyl carrier protein (BCCP) domain of acetyl-CoA carboxylase and converts it to active holo-BCCP (PubMed:18509457, PubMed:24723382). Forms an acyl-adenylate intermediate (PubMed:18509457, PubMed:24723382). Cannot use GTP or desthiobiotin (PubMed:18509457).<ref>PMID:18509457</ref> <ref>PMID:24723382</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 27: / Line 27: @@
 </StructureSection>
 [[Category: Large Structures]]
-[[Category: Finzel, B C]]
+[[Category: Mycobacterium tuberculosis]]
-[[Category: Mora-Rey, T De la]]
+[[Category: De la Mora-Rey T]]
-[[Category: Biotin-protein ligase]]
+[[Category: Finzel BC]]
-[[Category: Bisubstrate inhibitor]]
-[[Category: Ligase-ligase inhibitor complex]]

4xtw: Difference between revisions

Latest revision as of 07:49, 27 September 2023

Mycobacterium tuberculosis biotin ligase complexed with bisubstrate inhibitor 46 with azide in place of 2'OH

Structural highlights

Function

Publication Abstract from PubMed

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References

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