3nof | pdb_00003nof

Mycobacterium tuberculosis thioredoxin C C40S mutant

spinqualitylabelsall models 3nof, resolution 1.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3nof is a 2 chain structure with sequence from Mycobacterium tuberculosis H37Ra. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.6Å Ligands: SCN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A5U9P2_MYCTA Publication Abstract from PubMed Thioredoxin 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Thioredoxin 3D structures

Proteopedia Page Contributors and Editors (what is this?)

OCA