8HKR

Crystal Structure of Histone H3 Lysine 79 (H3K79) Methyltransferase Rv2067c from Mycobacterium tuberculosis

Summary for 8HKR

• Entry DOI: 10.2210/pdb8hkr/pdb
• Descriptor: Protein lysine methyltransferase, PHOSPHATE ION, S-ADENOSYL-L-HOMOCYSTEINE, ... (4 entities in total)
• Functional Keywords: mycobacterium tuberculosis, sam-binding, class i methyltransferase, dimerization domain, transferase
• Biological source: Mycobacterium tuberculosis H37Rv
• Total number of polymer chains: 2
• Total formula weight: 93392.05

Authors

Dadireddy, V.,Singh, P.R.,Kalladi, S.M.,Valakunja, N.,Ramakumar, S. (deposition date: 2022-11-28, release date: 2023-10-18, Last modification date: 2024-01-24)

Primary citation

Singh, P.R.,Dadireddy, V.,Udupa, S.,Kalladi, S.M.,Shee, S.,Khosla, S.,Rajmani, R.S.,Singh, A.,Ramakumar, S.,Nagaraja, V.
The Mycobacterium tuberculosis methyltransferase Rv2067c manipulates host epigenetic programming to promote its own survival.
Nat Commun, 14:8497-8497, 2023

PubMed Abstract: Mycobacterium tuberculosis has evolved several mechanisms to counter host defense arsenals for its proliferation. Here we report that M. tuberculosis employs a multi-pronged approach to modify host epigenetic machinery for its survival. It secretes methyltransferase (MTase) Rv2067c into macrophages, trimethylating histone H3K79 in a non-nucleosomal context. Rv2067c downregulates host MTase DOT1L, decreasing DOT1L-mediated nucleosomally added H3K79me3 mark on pro-inflammatory response genes. Consequent inhibition of caspase-8-dependent apoptosis and enhancement of RIPK3-mediated necrosis results in increased pathogenesis. In parallel, Rv2067c enhances the expression of SESTRIN3, NLRC3, and TMTC1, enabling the pathogen to overcome host inflammatory and oxidative responses. We provide the structural basis for differential methylation of H3K79 by Rv2067c and DOT1L. The structures of Rv2067c and DOT1L explain how their action on H3K79 is spatially and temporally separated, enabling Rv2067c to effectively intercept the host epigenetic circuit and downstream signaling.

PubMed: 38129415
DOI: 10.1038/s41467-023-43940-6

Experimental method

X-RAY DIFFRACTION (2.4 Å)