9M2P

Imidazole glycerol phosphate dehydratase from Mycobacterium tuberculosis, apo structure

Summary for 9M2P

• Entry DOI: 10.2210/pdb9m2p/pdb
• EMDB information: 63588 63589 63590
• Descriptor: Imidazoleglycerol-phosphate dehydratase, MANGANESE (II) ION (3 entities in total)
• Functional Keywords: histidine pathway, dehydratase, mycobacterium tuberculosis, lyase
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 24
• Total formula weight: 569841.41

Authors

Raina, R.,Kar, D.,Singla, M.,Tiwari, S.,Kumari, S.,Aneja, S.,Kumar, V.,Banerjee, S.,Goyal, S.,Pal, R.K.,Vinothkumar, K.R.,Biswal, B.K. (deposition date: 2025-02-28, release date: 2025-06-18)

Primary citation

Raina, R.,Kar, D.,Singla, M.,Tiwari, S.,Kumari, S.,Aneja, S.,Kumar, V.,Banerjee, S.,Goyal, S.,Pal, R.K.,Vinothkumar, K.R.,Biswal, B.
Cryo-EM structures of Mycobacterium tuberculosis imidazole glycerol phosphate dehydratase in the apo state and in the presence of small molecules.
Acta Crystallogr.,Sect.F, 2025

PubMed Abstract: Unlike humans, Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis, has a de novo histidine-biosynthesis pathway. The enzyme imidazole glycerol phosphate dehydratase (IGPD), which catalyses the conversion of imidazole glycerol phosphate to imidazole acetol phosphate, has been studied extensively from various organisms and has become a major target for the development of antibacterial, antiweed and antifungal small molecules. In our previous studies, we have shown that in crystals IGPD forms a 24-mer oligomeric state in which the monomers are arranged in 432 symmetry. In order to gain insights into the oligomeric state of Mtb IGPD in solution, we determined cryogenic sample electron microscopy (cryo-EM) structures of apo IGPD at 2.2 and 3.1 Å resolution. In addition, we also determined the cryo-EM structure of IGPD in the presence of 3-amino-1,2,4-triazole (ATZ) to 2.8 Å resolution. The results of this work, which corroborate those from the crystallographic studies, indicate that IGPD forms a homo-oligomeric structure in solution comprising of 24 subunits. ATZ binds in the active-site pocket of the enzyme, which is located at the interface of three monomers and tethers 24 ATZ molecules. The results of this study suggest that cryo-EM, in addition to being a rapidly evolving and complementary imaging technology for elucidating 3D structures of biological macromolecules, can be useful in pinpointing the mode of binding small molecules of low mass (here ∼85 Da) and mapping protein-ligand interactions, which could assist in the design of accurate (high-potency) inhibitors.

PubMed: 40478632
DOI: 10.1107/S2053230X25004595

Experimental method

ELECTRON MICROSCOPY (3.1 Å)