8ze4

From Proteopedia

MPXV mRNA cap N7 methyltransferase mutant-H122D

Structural highlights

8ze4 is a 2 chain structure with sequence from Monkeypox virus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.33Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MCEL_MONPV Catalytic subunit of the mRNA capping enzyme which catalyzes three enzymatic reactions: the 5' triphosphate end of the pre-mRNA is hydrolyzed to a diphosphate by RNA 5' triphosphatase; the diphosphate RNA end is capped with GMP by RNA guanylyltransferase and the GpppN cap is methylated by RNA (guanine-N7) methyltransferase. Heterodimeric mRNA capping enzyme catalyzes the linkage of a N7-methyl-guanosine moiety to the first transcribed nucleotide (cap 0 structure), whereas the methyltransferase OPG102 is responsible for a second methylation at the 2'-O position of the ribose (cap 1 structure). Also involved in early viral gene transcription termination and intermediate viral gene transcription initiation. Early gene transcription termination requires the termination factor VTF, the DNA-dependent ATPase NPH-I/OPG123 and the RAP94/OPG109 subunit of the viral RNA polymerase, as well as the presence of a specific termination motif. Binds, together with RAP94/OPG109, to the termination motif 5'-UUUUUNU-3' in the nascent early mRNA.[UniProtKB:P04298]

Publication Abstract from PubMed

The global outbreak of Mpox, caused by the monkeypox virus (MPXV), has attracted international attention and become another major infectious disease event after COVID-19. The mRNA cap N7 methyltransferase (RNMT) of MPXV methylates the N7 position of the added guanosine to the 5'-cap structure of mRNAs and plays a vital role in evading host antiviral immunity. MPXV RNMT is composed of the large subunit E1 and the small subunit E12. How E1 and E12 of MPXV assembly remains unclear. Here, we report the crystal structures of E12, the MTase domain of E1 with E12 (E1(CTD)-E12) complex, and the E1(CTD)-E12-SAM ternary complex, revealing the detailed conformations of critical residues and the structural changes upon E12 binding to E1. Functional studies suggest that E1(CTD) N-terminal extension (Asp545-Arg562) and the small subunit E12 play an essential role in the binding process of SAM. Structural comparison of the AlphaFold2-predicted E1, E1(CTD)-E12 complex, and the homologous D1-D12 complex of vaccinia virus (VACV) indicates an allosteric activating effect of E1 in MPXV. Our findings provide the structural basis for the MTase activity stimulation of the E1-E12 complex and suggest a potential interface for screening the anti-poxvirus inhibitors.

Structural basis of the monkeypox virus mRNA cap N7 methyltransferase complex.,Chen A, Fang N, Zhang Z, Wen Y, Shen Y, Zhang Y, Zhang L, Zhao G, Ding J, Li J Emerg Microbes Infect. 2024 Dec;13(1):2369193. doi: , 10.1080/22221751.2024.2369193. Epub 2024 Jun 27. PMID:38873898^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Chen A, Fang N, Zhang Z, Wen Y, Shen Y, Zhang Y, Zhang L, Zhao G, Ding J, Li J. Structural basis of the monkeypox virus mRNA cap N7 methyltransferase complex. Emerg Microbes Infect. 2024 Dec;13(1):2369193. PMID:38873898 doi:10.1080/22221751.2024.2369193