biostudies-literatureUnknownGupta MNIBIB NIH HHSNCRR NIH HHSNIA NIH HHSNIAID NIH HHSNIMH NIH HHSNCI NIH HHSNIGMS NIH HHSNIH HHSThe SARS-CoV-2 protein Nsp2 has been implicated in a wide range of viral processes, but its exact functions, and the structural basis of those functions, remain unknown. Here, we report an atomic model for full-length Nsp2 obtained by combining cryo-electron microscopy with deep learning-based structure prediction from AlphaFold2. The resulting structure reveals a highly-conserved zinc ion-binding site, suggesting a role for Nsp2 in RNA binding. Mapping emerging mutations from variants of SARS-CoV-2 on the resulting structure shows potential host-Nsp2 interaction regions. Using structural analysis together with affinity tagged purification mass spectrometry experiments, we identify Nsp2 mutants that are unable to interact with the actin-nucleation-promoting WASH protein complex or with GIGbioRxiv : the preprint server for biology2021.05.10.443524https://www.ebi.ac.uk/biostudies/studies/S-EPMC8132225biostudies-literatureCryoEM and AI reveal a structure of SARS-CoV-2 Nsp2, a multifunctional protein involved in key host processes.PMC8132225K99 MH119591S10 RR026814F32 GM133129U19 AI135990R01 GM024485T32 EB009383U19 AI135972R37 GM024485S10 OD026881F32 CA239333R35 GM118099T32 GM007618R01 AI128214K99 GM138753P50 AI150476P01 AI063302K99 AG070271S10 OD020054F30 CA247147R01 AI143292R01 AI120694F32 GM133084P01 AI095208S10 OD021741F32 GM137463Zhang KFraser JSWang FLopez KEFrost AThwin ACHernandez ESun MPelin ARemesh SGBillesbolle CSafari MDiwanji DDoan LJin MPeters JKDiallo AGupta MLinossi ETse EOwens TWVerba KAKrogan NJLi JChen JJang GLi FLi YLLi YPuchades CChen KHLo MMoritz MMoss FRSouthworth DRAzumaya CMTitus EWFossati ASmith AMSchaefer KZuliani-Alvarez LYoung IDTsui TKMQCRG Structural Biology ConsortiumKratochvil HTChio USKim KNowotny CPospiech THRosenberg OSCheng YBouhaddou MLiu YLopez JPawar KIRizo ANPaul MDTabios MCAsarnow DManglik AZhou FYu ZNguyen HCZhao JCampbell MGJura NLam VLMerz GEStroud RMHerrera NZhou YKortemme TDickinson MSZhang YSwaney DLBrilot AFSchulze-Gahmen UAgard DAPourmal STrenker RMancino AfalseCryoEM and AI reveal a structure of SARS-CoV-2 Nsp2, a multifunctional protein involved in key host processes.The SARS-CoV-2 protein Nsp2 has been implicated in a wide range of viral processes, but its exact functions, and the structural basis of those functions, remain unknown. Here, we report an atomic model for full-length Nsp2 obtained by combining cryo-electron microscopy with deep learning-based structure prediction from AlphaFold2. The resulting structure reveals a highly-conserved zinc ion-binding site, suggesting a role for Nsp2 in RNA binding. Mapping emerging mutations from variants of SARS-CoV-2 on the resulting structure shows potential host-Nsp2 interaction regions. Using structural analysis together with affinity tagged purification mass spectrometry experiments, we identify Nsp2 mutants that are unable to interact with the actin-nucleation-promoting WASH protein complex or with GIG2021-01-01T00:00:00Z2021 May2026-04-08T07:58:30.163Z2025-05-18T11:27:49.261ZS-EPMC81322253401326910.1101/2021.05.10.443524