4MQM

Crystal structure of Antigen 85C in presence of Ebselen

Summary for 4MQM

• Entry DOI: 10.2210/pdb4mqm/pdb
• Related: 4MQL
• Descriptor: Diacylglycerol acyltransferase/mycolyltransferase Ag85C (2 entities in total)
• Functional Keywords: acyltransferase, transferase
• Biological source: Mycobacterium tuberculosis
• Cellular location: Secreted (By similarity): P0A4V4
• Total number of polymer chains: 1
• Total formula weight: 33313.86

Authors

Favrot, L.,Grzegorzewicz, A.E.,Lajiness, D.H.,Marvin, R.K.,Boucau, J.,Isailovic, D.,Jackson, M.,Ronning, D.R. (deposition date: 2013-09-16, release date: 2013-11-13, Last modification date: 2024-02-28)

Primary citation

Favrot, L.,Grzegorzewicz, A.E.,Lajiness, D.H.,Marvin, R.K.,Boucau, J.,Isailovic, D.,Jackson, M.,Ronning, D.R.
Mechanism of inhibition of Mycobacterium tuberculosis antigen 85 by ebselen.
Nat Commun, 4:2748-2748, 2013

PubMed Abstract: The increasing prevalence of drug-resistant tuberculosis highlights the need for identifying new antitubercular drugs that can treat these infections. The antigen 85 (Ag85) complex has emerged as an intriguing mycobacterial drug target due to its central role in synthesizing major components of the inner and outer leaflets of the mycobacterial outer membrane. Here we identify ebselen (EBS) as a potent inhibitor of the Mycobacterium tuberculosis Ag85 complex. Mass spectrometry data show that EBS binds covalently to a cysteine residue (C209) located near the Ag85C active site. The crystal structure of Ag85C in the presence of EBS shows that C209 modification restructures the active site, thereby disrupting the hydrogen-bonded network within the active site that is essential for enzymatic activity. C209 mutations display marked decreases in enzymatic activity. These data suggest that compounds using this mechanism of action will strongly inhibit the Ag85 complex and minimize the selection of drug resistance.

PubMed: 24193546
DOI: 10.1038/ncomms3748

Experimental method

X-RAY DIFFRACTION (1.346 Å)