5f08

Structure of Transcriptional Regulatory Repressor Protein - EthR from Mycobacterium tuberculosis in complex with compound 14 at 1.92A resolutionStructure of Transcriptional Regulatory Repressor Protein - EthR from Mycobacterium tuberculosis in complex with compound 14 at 1.92A resolution

Structural highlights

5f08 is a 1 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 1.92Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ETHR_MYCTU Involved in the repression of the monooxygenase EthA which is responsible of the formation of the active metabolite of ethionamide (ETH).^[1] ^[2]

Publication Abstract from PubMed

With the ever-increasing instances of resistance to frontline TB drugs there is the need to develop novel strategies to fight the worldwide TB epidemic. Boosting the effect of the existing second-line antibiotic ethionamide by inhibiting the mycobacterial transcriptional repressor protein EthR is an attractive therapeutic strategy. Herein we report the use of a fragment based drug discovery approach for the structure-guided systematic merging of two fragment molecules, each binding twice to the hydrophobic cavity of EthR from M. tuberculosis. These together fill the entire binding pocket of EthR. We elaborated these fragment hits and developed small molecule inhibitors which have a 100-fold improvement of potency in vitro over the initial fragments.

A fragment merging approach towards the development of small molecule inhibitors of Mycobacterium tuberculosis EthR for use as ethionamide boosters.,Nikiforov PO, Surade S, Blaszczyk M, Delorme V, Brodin P, Baulard AR, Blundell TL, Abell C Org Biomol Chem. 2016 Jan 25. PMID:26806381^[3]

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

References

↑ Baulard AR, Betts JC, Engohang-Ndong J, Quan S, McAdam RA, Brennan PJ, Locht C, Besra GS. Activation of the pro-drug ethionamide is regulated in mycobacteria. J Biol Chem. 2000 Sep 8;275(36):28326-31. PMID:10869356 doi:10.1074/jbc.M003744200
↑ DeBarber AE, Mdluli K, Bosman M, Bekker LG, Barry CE 3rd. Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9677-82. PMID:10944230
↑ Nikiforov PO, Surade S, Blaszczyk M, Delorme V, Brodin P, Baulard AR, Blundell TL, Abell C. A fragment merging approach towards the development of small molecule inhibitors of Mycobacterium tuberculosis EthR for use as ethionamide boosters. Org Biomol Chem. 2016 Jan 25. PMID:26806381 doi:http://dx.doi.org/10.1039/c5ob02630j

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Baulard AR, Betts JC, Engohang-Ndong J, Quan S, McAdam RA, Brennan PJ, Locht C, Besra GS. Activation of the pro-drug ethionamide is regulated in mycobacteria. J Biol Chem. 2000 Sep 8;275(36):28326-31. PMID:10869356 doi:10.1074/jbc.M003744200

[2] DeBarber AE, Mdluli K, Bosman M, Bekker LG, Barry CE 3rd. Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9677-82. PMID:10944230

[3] Nikiforov PO, Surade S, Blaszczyk M, Delorme V, Brodin P, Baulard AR, Blundell TL, Abell C. A fragment merging approach towards the development of small molecule inhibitors of Mycobacterium tuberculosis EthR for use as ethionamide boosters. Org Biomol Chem. 2016 Jan 25. PMID:26806381 doi:http://dx.doi.org/10.1039/c5ob02630j

[1]

[2]

[3]