Journal Article

PUBDB-2026-01388

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Unlocking the secrets of SARS-CoV-2 nsp3 by combining experiments with AlphaFold2 domain prediction

Edich, M. ; Gao, Y. ; Briggs, D. C. ; Thorn, A. R. S. (Corresponding author)Extern*

2026
EMBO Press Heidelberg

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Please use a persistent id in citations: doi:10.26508/lsa.202503247  doi:10.3204/PUBDB-2026-01388

Abstract: Nonstructural protein 3 (nsp3) is crucial for SARS-CoV-2 infection. It is the largest protein of the virus with roughly 2000 residues, and a major drug target. However, because of its size, disordered regions, and transmembrane domains, the atomic structure of the whole protein has not yet been established. Only 10 out of its 16 domains were individually determined in experiments. Here, we demonstrate how structural bioinformatics, AI-based fold prediction, and traditional experiments complement each other and can shed light on the makeup of this important protein, both in SARS-CoV-2 and in related viruses. Our method can be generalized for other multidomain proteins. Our prediction-based approach reveals a previously undescribed folded domain, which we could confirm experimentally. Our research also suggests a potential function of the domain Y1: this domain may be involved in the assembly of nsp3, nsp4, and nsp6 into the hexameric pore, which was discovered by electron tomography and exports RNA into the cytosol. The Y1 hexamer, however, could not be expressed on its own. We revise domain segmentation and nomenclature of nsp3 domains.

Note: DeutscheForschungsgemeinschaft (project TH2135/2-1).

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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)
2. 05K22GU5 - Neue KI-basierte, visuelle und automatische Analysemethoden für die makromolekulare Strukturbestimmung an Großgeräten: AUSPEX (BMBF-05K22GU5) (BMBF-05K22GU5)

Experiment(s):

1. PETRA Beamline P12 (PETRA III)

Appears in the scientific report 2026

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