5oep: Difference between revisions

Revision as of 12:22, 26 August 2020

Mycobacterium tuberculosis DprE1 in complex with inhibitor TCA481

Structural highlights

5oep is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	9T2, FAD, IMD
Related:	4kw5, 5oel
Activity:	Decaprenylphospho-beta-D-ribofuranose 2-oxidase, with EC number 1.1.98.3
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[DPRE1_MYCTU] Involved in the epimerization of decaprenylphosphoryl ribose (DPR) to decaprenylphosphoryl arabinose (DPA) a precursor for arabinan synthesis in mycobacterial cell wall biosynthesis. Probably catalyzes the oxidation at C-2 of decaprenylphosphoryl ribose (DPR) to yield decaprenylphosphoryl 2-keto-ribose (DPX).^[1]

Publication Abstract from PubMed

Mycobacterium tuberculosis (Mtb) DprE1, an essential isomerase for the biosynthesis of the mycobacterial cell wall, is a validated target for tuberculosis (TB) drug development. Here we report the X-ray crystal structures of DprE1 and the DprE1 resistant mutant (Y314C) in complexes with TCA1 derivatives to elucidate the molecular basis of their inhibitory activities and an unconventional resistance mechanism, which enabled us to optimize the potency of the analogs. The selected lead compound showed excellent in vitro and in vivo activities, and low risk of toxicity profile except for the inhibition of CYP2C9. A crystal structure of CYP2C9 in complex with a TCA1 analog revealed the similar interaction patterns to the DprE1-TCA1 complex. Guided by the structures, an optimized molecule was generated with differential inhibitory activities against DprE1 and CYP2C9, which provides insights for development of a clinical candidate to treat TB.

Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes.,Liu R, Lyu X, Batt SM, Hsu MH, Harbut MB, Vilcheze C, Cheng B, Ajayi K, Yang B, Yang Y, Guo H, Lin C, Gan F, Wang C, Franzblau SG, Jacobs WR Jr, Besra GS, Johnson EF, Petrassi M, Chatterjee AK, Futterer K, Wang F Angew Chem Int Ed Engl. 2017 Aug 16. doi: 10.1002/anie.201707324. PMID:28815830^[2]

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

References

↑ Mikusova K, Huang H, Yagi T, Holsters M, Vereecke D, D'Haeze W, Scherman MS, Brennan PJ, McNeil MR, Crick DC. Decaprenylphosphoryl arabinofuranose, the donor of the D-arabinofuranosyl residues of mycobacterial arabinan, is formed via a two-step epimerization of decaprenylphosphoryl ribose. J Bacteriol. 2005 Dec;187(23):8020-5. PMID:16291675 doi:https://dx.doi.org/10.1128/JB.187.23.8020-8025.2005
↑ Liu R, Lyu X, Batt SM, Hsu MH, Harbut MB, Vilcheze C, Cheng B, Ajayi K, Yang B, Yang Y, Guo H, Lin C, Gan F, Wang C, Franzblau SG, Jacobs WR Jr, Besra GS, Johnson EF, Petrassi M, Chatterjee AK, Futterer K, Wang F. Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes. Angew Chem Int Ed Engl. 2017 Aug 16. doi: 10.1002/anie.201707324. PMID:28815830 doi:https://dx.doi.org/10.1002/anie.201707324

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OCA

[1] Mikusova K, Huang H, Yagi T, Holsters M, Vereecke D, D'Haeze W, Scherman MS, Brennan PJ, McNeil MR, Crick DC. Decaprenylphosphoryl arabinofuranose, the donor of the D-arabinofuranosyl residues of mycobacterial arabinan, is formed via a two-step epimerization of decaprenylphosphoryl ribose. J Bacteriol. 2005 Dec;187(23):8020-5. PMID:16291675 doi:https://dx.doi.org/10.1128/JB.187.23.8020-8025.2005

[2] Liu R, Lyu X, Batt SM, Hsu MH, Harbut MB, Vilcheze C, Cheng B, Ajayi K, Yang B, Yang Y, Guo H, Lin C, Gan F, Wang C, Franzblau SG, Jacobs WR Jr, Besra GS, Johnson EF, Petrassi M, Chatterjee AK, Futterer K, Wang F. Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes. Angew Chem Int Ed Engl. 2017 Aug 16. doi: 10.1002/anie.201707324. PMID:28815830 doi:https://dx.doi.org/10.1002/anie.201707324

[1]

[2]

@@ Line 1: / Line 1: @@
 ==Mycobacterium tuberculosis DprE1 in complex with inhibitor TCA481==
-<StructureSection load='5oep' size='340' side='right' caption='[[5oep]], [[Resolution|resolution]] 2.35&Aring;' scene=''>
+<StructureSection load='5oep' size='340' side='right'caption='[[5oep]], [[Resolution|resolution]] 2.35&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5oep]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OEP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5OEP FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5oep]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OEP OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5OEP FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9T2:ethyl+~{N}-[2-(1,3-benzothiazol-2-ylcarbonylamino)-5-fluoranyl-thiophen-3-yl]carbonylcarbamate'>9T2</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9T2:ethyl+~{N}-[2-(1,3-benzothiazol-2-ylcarbonylamino)-5-fluoranyl-thiophen-3-yl]carbonylcarbamate'>9T2</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4kw5|4kw5]], [[5oel|5oel]]</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Decaprenylphospho-beta-D-ribofuranose_2-oxidase Decaprenylphospho-beta-D-ribofuranose 2-oxidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.98.3 1.1.98.3] </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=5oep FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5oep OCA], [http://pdbe.org/5oep PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5oep RCSB], [http://www.ebi.ac.uk/pdbsum/5oep PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5oep ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5oep FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5oep OCA], [http://pdbe.org/5oep PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5oep RCSB], [http://www.ebi.ac.uk/pdbsum/5oep PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5oep ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 25: / Line 25: @@
 </StructureSection>
 [[Category: Decaprenylphospho-beta-D-ribofuranose 2-oxidase]]
+[[Category: Large Structures]]
 [[Category: Batt, S M]]
 [[Category: Besra, G S]]

5oep: Difference between revisions

Revision as of 12:22, 26 August 2020

Mycobacterium tuberculosis DprE1 in complex with inhibitor TCA481

Structural highlights

Function

Publication Abstract from PubMed

References

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