PDBsum entry 4w1v

Transferase/transferase inhibitor

PDB id: 4w1v

Contents

Protein chains

425 a.a.

Ligands

PLP ×2

3GS ×2

PEG

EDO ×4

Metals

_CL

Waters ×383

PDB id:

4w1v

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of 7,8-diaminopelargonic acid synthase (bioa) from mycobacterium tuberculosis, complexed with a thiazole inhibitor

Structure:

Adenosylmethionine-8-amino-7-oxononanoate aminotransferase. Chain: a, b. Synonym: 7,8-diamino-pelargonic acid aminotransferase,dapa aminotransferase,8-diaminononanoate synthase,dans,diaminopelargonic acid synthase. Engineered: yes

Source:

Mycobacterium tuberculosis. Organism_taxid: 83331. Strain: cdc 1551 / oshkosh. Gene: bioa, mt1619. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.24Å R-factor: 0.172 R-free: 0.210

Authors:

B.C.Finzel,R.Dai

Key ref:

S.W.Park et al. (2015). Target-based identification of whole-cell active inhibitors of biotin biosynthesis in Mycobacterium tuberculosis. Chem Biol, 22, 76-86. PubMed id: 25556942 DOI: 10.1016/j.chembiol.2014.11.012

Date:

13-Aug-14 Release date: 04-Feb-15

Protein chains

P9WQ80  (BIOA_MYCTO) -  Adenosylmethionine-8-amino-7-oxononanoate aminotransferase from Mycobacterium tuberculosis (strain CDC 1551 / Oshkosh)

Seq: 437 a.a.

Struc: 425 a.a.

Enzyme reactions

• Enzyme class: E.C.2.6.1.62 - adenosylmethionine--8-amino-7-oxononanoate transaminase.
• Reaction: (8S)-8-amino-7-oxononanoate + S-adenosyl-L-methionine = S-adenosyl-4- methylsulfanyl-2-oxobutanoate + (7R,8S)-7,8-diammoniononanoate
• Cofactor: Pyridoxal 5'-phosphate

Pyridoxal 5'-phosphate (Bound ligand (Het Group name = PLP) matches with 93.75% similarity)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1016/j.chembiol.2014.11.012

Chem Biol 22:76-86 (2015)

PubMed id: 25556942

Target-based identification of whole-cell active inhibitors of biotin biosynthesis in Mycobacterium tuberculosis.

S.W.Park, D.E.Casalena, D.J.Wilson, R.Dai, P.P.Nag, F.Liu, J.P.Boyce, J.A.Bittker, S.L.Schreiber, B.C.Finzel, D.Schnappinger, C.C.Aldrich.

ABSTRACT

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.