Structural basis for dimerization of a paramyxovirus polymerase complex

Jin Xie, Mohamed Ouizougun-Oubari, Li Wang, Guanglei Zhai, Daitze Wu, Zhaohu Lin, Manfu Wang, Barbara Ludeke, Xiaodong Yan, Tobias Nilsson, Lu Gao (), Xinyi Huang (), Rachel Fearns () and Shuai Chen ()
Additional contact information
Jin Xie: Lead Discovery, Roche Innovation Center Shanghai
Mohamed Ouizougun-Oubari: Boston University Chobanian & Avedisian School of Medicine
Li Wang: Infectious Diseases, Roche Innovation Center Shanghai
Guanglei Zhai: Lead Discovery, Roche Innovation Center Shanghai
Daitze Wu: Infectious Diseases, Roche Innovation Center Shanghai
Zhaohu Lin: Lead Discovery, Roche Innovation Center Shanghai
Manfu Wang: Wuxi Biortus Biosciences Co. Ltd.
Barbara Ludeke: Boston University Chobanian & Avedisian School of Medicine
Xiaodong Yan: Wuxi Biortus Biosciences Co. Ltd.
Tobias Nilsson: Infectious Diseases, Roche Innovation Center Basel
Lu Gao: Infectious Diseases, Roche Innovation Center Shanghai
Xinyi Huang: Lead Discovery, Roche Innovation Center Shanghai
Rachel Fearns: Boston University Chobanian & Avedisian School of Medicine
Shuai Chen: Lead Discovery, Roche Innovation Center Shanghai

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-47470-7

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