7JT5

Mycobacterium tuberculosis dethiobiotin synthetase in complex with fragment analogue 9

Summary for 7JT5

• Entry DOI: 10.2210/pdb7jt5/pdb
• Related: 6NLZ 6NMZ 6NNZ 6NU6 6NVC 6NVE 6NVF 6NWG
• Descriptor: ATP-dependent dethiobiotin synthetase BioD, GLYCEROL, {(1R,2R)-2-[4-(carboxymethyl)benzene-1-carbonyl]cyclopentyl}propanedioic acid, ... (5 entities in total)
• Functional Keywords: inhibitor, ligase, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Biological source: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• Total number of polymer chains: 4
• Total formula weight: 95905.01

Authors

Pederick, J.P.,Bruning, J.B. (deposition date: 2020-08-17, release date: 2021-09-08, Last modification date: 2023-10-18)

Primary citation

Schumann, N.C.,Lee, K.J.,Thompson, A.P.,Salaemae, W.,Pederick, J.L.,Avery, T.,Gaiser, B.I.,Hodgkinson-Bean, J.,Booker, G.W.,Polyak, S.W.,Bruning, J.B.,Wegener, K.L.,Abell, A.D.
Inhibition of Mycobacterium tuberculosis Dethiobiotin Synthase ( Mt DTBS): Toward Next-Generation Antituberculosis Agents.
Acs Chem.Biol., 16:2339-2347, 2021

PubMed Abstract: dethiobiotin synthase (DTBS) is a crucial enzyme involved in the biosynthesis of biotin in the causative agent of tuberculosis, . Here, we report a binder of DTBS, cyclopentylacetic acid ( = 3.4 ± 0.4 mM), identified screening. X-ray crystallography showed that binds in the 7,8-diaminopelargonic acid (DAPA) pocket of DTBS. Appending an acidic group to the para-position of the aromatic ring of the scaffold revealed compounds and as more potent binders, with = 19 ± 5 and 17 ± 1 μM, respectively. Further optimization identified tetrazole as a particularly potent binder ( = 57 ± 5 nM) and inhibitor ( = 5 ± 1 μM) of DTBS. Our findings highlight the first reported inhibitors of DTBS and serve as a platform for the further development of potent inhibitors and novel therapeutics for the treatment of tuberculosis.

PubMed: 34533923
DOI: 10.1021/acschembio.1c00491

Experimental method

X-RAY DIFFRACTION (2 Å)