4OOB

Crystal structure of HtdX(Rv0241c) from Mycobacterium tuberculosis

Summary for 4OOB

• Entry DOI: 10.2210/pdb4oob/pdb
• Descriptor: Uncharacterized protein HtdX, CHLORIDE ION (3 entities in total)
• Functional Keywords: hotdog fold, oxidoreductase
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 1
• Total formula weight: 28339.93

Authors

Biswas, R.,Dutta, D.,Das, A.K. (deposition date: 2014-01-31, release date: 2015-02-04, Last modification date: 2025-06-25)

Primary citation

Biswas, R.,Bhattacharje, G.,Singh, B.K.,Dutta, D.,Basak, A.,Das, A.K.
Crystal structure and molecular dynamics simulation of Mycobacterium tuberculosis MaoC-like dehydratase HtdX provide insights into substrate binding and membrane interactions.
Biochim Biophys Acta Proteins Proteom, 1873:141082-141082, 2025

PubMed Abstract: The growing challenge of drug resistance has intensified the search for new therapeutic targets against the virulent pathogen Mycobacterium tuberculosis (Mtb). The complex cell envelope of Mtb contains unique lipids, such as mycolic acids, which contribute to its survival under hostile conditions. While modern drugs like isoniazid inhibit mycolic acid biosynthesis through the fatty acid synthase II (FAS II) complex, alternative bypass pathways may facilitate the emergence of drug resistance. HtdX, a putative β-hydroxyacyl dehydratase gene conserved in the mycobacterial species, is hypothesized to play a role in these alternative fatty acid metabolism pathways. Although HtdX is expressed under nutrient-deficient conditions, its structural and functional characterization remains largely unexplored. This study presents the crystal structures of HtdX, revealing a MaoC-like dehydratase with a double hot-dog fold. Site-directed mutagenesis, enzyme kinetics, and fluorescence spectroscopy highlight the critical roles of the α2-β2 loop and the proline rich PP-loop in substrate specificity. The α2-β2 loop determines fatty acyl chain length specificity, while the PP-loop regulates the interaction between HtdX and the acyl carrier protein (AcpM). Computational predictions, complemented by molecular dynamics simulations and principal component analyses, establish that the N-terminal region of HtdX is essential for membrane binding. Overall, these findings offer insights into HtdX substrate specificity and provide theoretical understanding of its interaction with the membrane.

PubMed: 40466754
DOI: 10.1016/j.bbapap.2025.141082

Experimental method

X-RAY DIFFRACTION (2.3 Å)