3o6t
Mycobacterium tuberculosis thioredoxin C C40S mutant in Complex with Quinol Inhibitor PMX464Mycobacterium tuberculosis thioredoxin C C40S mutant in Complex with Quinol Inhibitor PMX464
Structural highlights
FunctionTHIO_MYCTU Participates in various redox reactions through the reversible oxidation of its active center dithiol to a disulfide and catalyzes dithiol-disulfide exchange reactions (By similarity). Publication Abstract from PubMedThioredoxin plays a critical role in the regulation of cellular redox homeostasis. Many disease causing pathogens rely on the thioredoxin redox system for survival in conditions of environmental stress. The thioredoxin redox system has been implicated in the resistance of Mycobacterium tuberculosis (Mtb) to phagocytosis. Thioredoxin is able to reduce a variety of target substrates and reactive oxygen species (ROS) through the cyclisation of its active site dithiol to the oxidised disulphide Cys37-Cys40. Here we report the crystal structure of the Mtb thioredoxin C active site mutant C40S (MtbTrxCC40S) in isolation and in complex with the hydroxycyclohexadienone inhibitor PMX464. We observe PMX464 is covalently bound to the active site residue Cys37 through Michael addition of the cyclohexadienone ring and also forms non covalent contacts which mimic the binding of natural thioredoxin ligands. In comparison to the ligand free MtbTrxCC40S structure a conformational change occurs in the PMX464 complex involving movement of helix alpha2 and the active site loop. These changes are almost identical to those observed for helix alpha2 in human thioredoxin ligand complexes. Whereas the ligand free structure forms a homodimer the inhibitor complex unexpectedly forms a different dimer with one PMX464 molecule bound at the interface. This 2:1 MtbTrxCC40S-PMX464 complex is also observed using mass spectrometry measurements. This structure provides an unexpected scaffold for the design of improved thioredoxin inhibitors targeted at developing treatments for tuberculosis.Statement: Mycobacterium tuberculosis is the causative agent of tuberculosis. This bacterium relies on the protein thioredoxin for survival and this provides a suitable target for therapeutic intervention using an inhibitor. Our findings describe the first structure of thioredoxin in complex with an inhibitor. This provides a template for novel antibiotic development. Structure of Mycobacterium tuberculosis thioredoxin in complex with quinol inhibitor PMX464.,Hall G, Bradshaw TD, Laughton CA, Stevens MF, Emsley J Protein Sci. 2010 Oct 27. PMID:20981751[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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