3WQM

Crystal structure of Rv3378c with inhibitor BPH-629

Summary for 3WQM

• Entry DOI: 10.2210/pdb3wqm/pdb
• Related: 3WQK 3WQL 3WQN
• Descriptor: Diterpene synthase, [2-(3-DIBENZOFURAN-4-YL-PHENYL)-1-HYDROXY-1-PHOSPHONO-ETHYL]-PHOSPHONIC ACID, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: diterpene synthase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 1
• Total formula weight: 35523.69

Authors

Chan, H.C.,Feng, X.,Ko, T.P.,Huang, C.H.,Hu, Y.,Zheng, Y.,Bogue, S.,Nakano, C.,Hoshino, T.,Zhang, L.,Lv, P.,Liu, W.,Crick, D.C.,Liang, P.H.,Wang, A.H.,Oldfield, E.,Guo, R.T. (deposition date: 2014-01-28, release date: 2014-02-26, Last modification date: 2023-11-08)

Primary citation

Chan, H.C.,Feng, X.,Ko, T.P.,Huang, C.H.,Hu, Y.,Zheng, Y.,Bogue, S.,Nakano, C.,Hoshino, T.,Zhang, L.,Lv, P.,Liu, W.,Crick, D.C.,Liang, P.H.,Wang, A.H.,Oldfield, E.,Guo, R.T.
Structure and inhibition of tuberculosinol synthase and decaprenyl diphosphate synthase from Mycobacterium tuberculosis.
J.Am.Chem.Soc., 136:2892-2896, 2014

PubMed Abstract: We have obtained the structure of the bacterial diterpene synthase, tuberculosinol/iso-tuberculosinol synthase (Rv3378c) from Mycobacterium tuberculosis , a target for anti-infective therapies that block virulence factor formation. This phosphatase adopts the same fold as found in the Z- or cis-prenyltransferases. We also obtained structures containing the tuberculosinyl diphosphate substrate together with one bisphosphonate inhibitor-bound structure. These structures together with the results of site-directed mutagenesis suggest an unusual mechanism of action involving two Tyr residues. Given the similarity in local and global structure between Rv3378c and the M. tuberculosis cis-decaprenyl diphosphate synthase (DPPS; Rv2361c), the possibility exists for the development of inhibitors that target not only virulence but also cell wall biosynthesis, based in part on the structures reported here.

PubMed: 24475925
DOI: 10.1021/ja413127v

Experimental method

X-RAY DIFFRACTION (2.1 Å)