4w1w

From Proteopedia

Crystal structure of 7,8-diaminopelargonic acid synthase (BioA) from Mycobacterium tuberculosis, complexed with 7-(diethylamino)-3-(thiophene-2-carbonyl)-2H-chromen-2-one

PDB ID 4w1w

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Structural highlights

4w1w 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 1.9Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

BIOA_MYCTO Catalyzes the 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 (By similarity).

Publication Abstract from PubMed

Biotin biosynthesis is essential for survival and persistence of Mycobacterium tuberculosis (Mtb) in vivo. The aminotransferase BioA, which catalyzes the antepenultimate step in the biotin pathway, has been established as a promising target due to its vulnerability to chemical inhibition. We performed high-throughput screening (HTS) employing a fluorescence displacement assay and identified a diverse set of potent inhibitors including many diversity-oriented synthesis (DOS) scaffolds. To efficiently select only hits targeting biotin biosynthesis, we then deployed a whole-cell counterscreen in biotin-free and biotin-containing medium against wild-type Mtb and in parallel with isogenic bioA Mtb strains that possess differential levels of BioA expression. This counterscreen proved crucial to filter out compounds whose whole-cell activity was off target as well as identify hits with weak, but measurable whole-cell activity in BioA-depleted strains. Several of the most promising hits were cocrystallized with BioA to provide a framework for future structure-based drug design efforts.

Target-Based Identification of Whole-Cell Active Inhibitors of Biotin Biosynthesis in Mycobacterium tuberculosis.,Park SW, Casalena DE, Wilson DJ, Dai R, Nag PP, Liu F, Boyce JP, Bittker JA, Schreiber SL, Finzel BC, Schnappinger D, Aldrich CC Chem Biol. 2015 Jan 22;22(1):76-86. doi: 10.1016/j.chembiol.2014.11.012. Epub, 2014 Dec 31. PMID:25556942^[1]

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

References

↑ Park SW, Casalena DE, Wilson DJ, Dai R, Nag PP, Liu F, Boyce JP, Bittker JA, Schreiber SL, Finzel BC, Schnappinger D, Aldrich CC. Target-Based Identification of Whole-Cell Active Inhibitors of Biotin Biosynthesis in Mycobacterium tuberculosis. Chem Biol. 2015 Jan 22;22(1):76-86. doi: 10.1016/j.chembiol.2014.11.012. Epub, 2014 Dec 31. PMID:25556942 doi:http://dx.doi.org/10.1016/j.chembiol.2014.11.012