5oel

From Proteopedia

(Difference between revisions)

Current revision

Mycobacterium tuberculosis DprE1 mutant Y314C in complex with TCA1

Structural highlights

5oel is a 2 chain structure with sequence from Mycobacterium tuberculosis CDC1551. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.2Å
Ligands:	,
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:http://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:http://dx.doi.org/10.1002/anie.201707324

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5oel"

Categories: Large Structures | Mycobacterium tuberculosis CDC1551 | Batt SM | Besra GS | Futterer K

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 5oel is ON HOLD  until Paper Publication
+==Mycobacterium tuberculosis DprE1 mutant Y314C in complex with TCA1==
+<StructureSection load='5oel' size='340' side='right'caption='[[5oel]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5oel]] 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=5OEL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5OEL 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]] 2.2&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1W6:ETHYL+({2-[(1,3-BENZOTHIAZOL-2-YLCARBONYL)AMINO]THIOPHEN-3-YL}CARBONYL)CARBAMATE'>1W6</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</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=5oel FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5oel OCA], [https://pdbe.org/5oel PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5oel RCSB], [https://www.ebi.ac.uk/pdbsum/5oel PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5oel ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/DPRE1_MYCTU 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).<ref>PMID:16291675</ref>
+<div style="background-color:#fffaf0;">
+== 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.
-Authors: Futterer, K., Batt, S.M., Besra, G.S.
+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<ref>PMID:28815830</ref>
-Description: Mycobacterium tuberculosis DprE1 mutant Y314C in complex with TCA1
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Besra, G.S]]
+<div class="pdbe-citations 5oel" style="background-color:#fffaf0;"></div>
-[[Category: Batt, S.M]]
+== References ==
-[[Category: Futterer, K]]
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Large Structures]]
+[[Category: Mycobacterium tuberculosis CDC1551]]
+[[Category: Batt SM]]
+[[Category: Besra GS]]
+[[Category: Futterer K]]

5oel

From Proteopedia

Current revision

Mycobacterium tuberculosis DprE1 mutant Y314C in complex with TCA1

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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