Structural basis for dimerization of a paramyxovirus polymerase complex.

Autor: Xie J; Roche Pharma Research and Early Development, Lead Discovery, Roche Innovation Center Shanghai, 201203, Shanghai, China., Ouizougun-Oubari M; Department of Virology, Immunology & Microbiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, 02118, USA., Wang L; Roche Pharma Research and Early Development, Infectious Diseases, Roche Innovation Center Shanghai, 201203, Shanghai, China., Zhai G; Roche Pharma Research and Early Development, Lead Discovery, Roche Innovation Center Shanghai, 201203, Shanghai, China., Wu D; Roche Pharma Research and Early Development, Infectious Diseases, Roche Innovation Center Shanghai, 201203, Shanghai, China., Lin Z; Roche Pharma Research and Early Development, Lead Discovery, Roche Innovation Center Shanghai, 201203, Shanghai, China., Wang M; Wuxi Biortus Biosciences Co. Ltd., 214437, Jiangyin, Jiangsu, China., Ludeke B; Department of Virology, Immunology & Microbiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, 02118, USA., Yan X; Wuxi Biortus Biosciences Co. Ltd., 214437, Jiangyin, Jiangsu, China., Nilsson T; Roche Pharma Research and Early Development, Infectious Diseases, Roche Innovation Center Basel, Basel, 4070, Switzerland., Gao L; Roche Pharma Research and Early Development, Infectious Diseases, Roche Innovation Center Shanghai, 201203, Shanghai, China. goodlucksept2016@yahoo.com., Huang X; Roche Pharma Research and Early Development, Lead Discovery, Roche Innovation Center Shanghai, 201203, Shanghai, China. xinyi.huang@roche.com., Fearns R; Department of Virology, Immunology & Microbiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, 02118, USA. rfearns@bu.edu., Chen S; Roche Pharma Research and Early Development, Lead Discovery, Roche Innovation Center Shanghai, 201203, Shanghai, China. shuai.chen.sc1@roche.com.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Apr 11; Vol. 15 (1), pp. 3163. Date of Electronic Publication: 2024 Apr 11.
DOI: 10.1038/s41467-024-47470-7
Abstrakt: The transcription and replication processes of non-segmented, negative-strand RNA viruses (nsNSVs) are catalyzed by a multi-functional polymerase complex composed of the large protein (L) and a cofactor protein, such as phosphoprotein (P). Previous studies have shown that the nsNSV polymerase can adopt a dimeric form, however, the structure of the dimer and its function are poorly understood. Here we determine a 2.7 Å cryo-EM structure of human parainfluenza virus type 3 (hPIV3) L-P complex with the connector domain (CD') of a second L built, while reconstruction of the rest of the second L-P obtains a low-resolution map of the ring-like L core region. This study reveals detailed atomic features of nsNSV polymerase active site and distinct conformation of hPIV3 L with a unique β-strand latch. Furthermore, we report the structural basis of L-L dimerization, with CD' located at the putative template entry of the adjoining L. Disruption of the L-L interface causes a defect in RNA replication that can be overcome by complementation, demonstrating that L dimerization is necessary for hPIV3 genome replication. These findings provide further insight into how nsNSV polymerases perform their functions, and suggest a new avenue for rational drug design.
(© 2024. The Author(s).)
Databáze: MEDLINE
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