The presence of exported chorismate mutases produced by certain organisms such as Mycobacterium tuberculosis has been shown to correlate with their pathogenicity. As such, these proteins comprise a new group of promising selective drug targets. Here, we report the high-resolution crystal structure of the secreted dimeric chorismate mutase from M. tuberculosis (*MtCM; encoded by Rv1885c), which represents the first 3D-structure of a member of this chorismate mutase family, termed the AroQγ subclass. Structures are presented both for the unliganded enzyme and for a complex with a transition state analog. The protomer fold resembles the structurally characterized (dimeric) Escherichia coli chorismate mutase domain, but exhibits a new topology, with helix H4 of*MtCM carrying the catalytic site residue missing in the shortened helix H1. Furthermore, the structure of each*MtCM protomer is significantly more compact and only harbors one active site pocket, which is formed entirely by one polypeptide chain. Apart from the structural model, we present evidence as to how the substrate may enter the active site.
Bibliographical noteFunding Information:
We thank Rosalino Pulido for the synthesis of inhibitor 1 . At the synchrotron beamlines ID14-4, ESRF, Grenoble and I-711, Max II, Lund, we had excellent support by Raimond Ravelli and Yngve Cerenius, respectively. This work has been supported by grants from the Carl Trygger foundation (research grant no. 02:158 to U.K. and a two-year postdoctoral fellowship to R.D.), from the Glycoconjugates in Biological Systems program of the Swedish National Foundation for Strategic Research (research position of U.K.), from Novartis Pharma (to S.S.), EMBIO (to E.G.), the University of Oslo (to U.K.) and the ETH Zürich (to P.K.).
- Crystal structure
- Pathogenic bacterium
- Permutated fold
- Secreted AroQ-class chorismate mutase
- Transition state analog complex