4MQQ

Mycobaterium tuberculosis transaminase BioA complexed with benzo[d]thiazole-2-carbohydrazide

Summary for 4MQQ

• Entry DOI: 10.2210/pdb4mqq/pdb
• Related: 4MQN 4MQO 4MQP 4MQR
• Descriptor: Adenosylmethionine-8-amino-7-oxononanoate aminotransferase, 1,2-ETHANEDIOL, CHLORIDE ION, ... (6 entities in total)
• Functional Keywords: plp, transaminase, transferase
• Biological source: Mycobacterium tuberculosis
• Cellular location: Cytoplasm (By similarity): P0A4X6
• Total number of polymer chains: 2
• Total formula weight: 98270.55

Authors

Finzel, B.C.,Dai, R. (deposition date: 2013-09-16, release date: 2014-03-05, Last modification date: 2023-09-20)

Primary citation

Dai, R.,Wilson, D.J.,Geders, T.W.,Aldrich, C.C.,Finzel, B.C.
Inhibition of Mycobacterium tuberculosis Transaminase BioA by Aryl Hydrazines and Hydrazides.
Chembiochem, 15:575-586, 2014

PubMed Abstract: 7,8-Diaminopelargonic acid synthase (BioA) of Mycobacterium tuberculosis is a recently validated target for therapeutic intervention in the treatment of tuberculosis (TB). Using biophysical fragment screening and structural characterization of compounds, we have identified a potent aryl hydrazine inhibitor of BioA that reversibly modifies the pyridoxal-5'-phosphate (PLP) cofactor, forming a stable quinonoid. Analogous hydrazides also form covalent adducts that can be observed crystallographically but are incapable of inactivating the enzyme. In the X-ray crystal structures, small molecules induce unexpected conformational remodeling in the substrate binding site. We compared these conformational changes to those induced upon binding of the substrate (7-keto-8-aminopelargonic acid), and characterized the inhibition kinetics and the X-ray crystal structures of BioA with the hydrazine compound and analogues to unveil the mechanism of this reversible covalent modification.

PubMed: 24482078
DOI: 10.1002/cbic.201300748

Experimental method

X-RAY DIFFRACTION (1.7 Å)