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TitleStructural basis for the assembly of the DNA polymerase holoenzyme from a monkeypox virus variant.
Journal, issue, pagesSci Adv, Vol. 9, Issue 16, Page eadg2331, Year 2023
Publish dateApr 21, 2023
AuthorsYaning Li / Yaping Shen / Ziwei Hu / Renhong Yan /
PubMed AbstractThe ongoing global pandemic caused by a variant of the monkeypox (or mpox) virus (MPXV) has prompted widespread concern. The MPXV DNA polymerase holoenzyme, consisting of F8, A22, and E4, is vital ...The ongoing global pandemic caused by a variant of the monkeypox (or mpox) virus (MPXV) has prompted widespread concern. The MPXV DNA polymerase holoenzyme, consisting of F8, A22, and E4, is vital for replicating the viral genome and represents a crucial target for the development of antiviral drugs. However, the assembly and working mechanism for the DNA polymerase holoenzyme of MPXV remains elusive. Here, we present the cryo-electron microscopy (cryo-EM) structure of the DNA polymerase holoenzyme at an overall resolution of 3.5 Å. Unexpectedly, the holoenzyme is assembled as a dimer of heterotrimers, of which the extra interface between the thumb domain of F8 and A22 shows a clash between A22 and substrate DNA, suggesting an autoinhibition state. Addition of exogenous double-stranded DNA shifts the hexamer into trimer exposing DNA binding sites, potentially representing a more active state. Our findings provide crucial steps toward developing targeted antiviral therapies for MPXV and related viruses.
External linksSci Adv / PubMed:37075110 / PubMed Central
MethodsEM (single particle)
Resolution3.1 - 3.5 Å
Structure data

EMDB-34885: F8-A22-E4 complex in hexameric form local map
Method: EM (single particle) / Resolution: 3.3 Å

34886

8hlz

EMDB-34886, PDB-8hlz:
F8-A22-E4 complex of MPXV in hexameric form
Method: EM (single particle) / Resolution: 3.5 Å

34887

8hm0

EMDB-34887, PDB-8hm0:
F8-A22-E4 complex of MPXV in trimeric form
Method: EM (single particle) / Resolution: 3.1 Å

Source
  • monkeypox virus
KeywordsREPLICATION / MPXV / complex / RECOMBINATION

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