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Nsp1 is found binding with the 40S ribosomal subunit and inhibiting the translation process, as well as docking with different cyclophilins. Herein, we evaluated the structural physicochemical properties of SARS-CoV-2 Nsp1 protein implementing different computational techniques. The Nsp1 was found to form a structured \u03b1-helical C-terminal region, following a conformational switch at residue S166 that is necessary for binding the 40S ribosome subunit. Similarly, the presence of cyclophilins stabilizes the Nsp1 C-terminus making a tilt movement at position 166. In the 40S ribosome-Nsp1 machinery, both the ribosomal uS3 and eS30 components were found equally interacting with Nsp1, which guided construction of their pharmacophores. Among a set of studied cyclophilins, FKBP1B showed the highest affinity with Nsp1 and PPIH made least interactions. The majority of cyclophilins dock to the conserved Nsp1 loop or linker region, which connects the C-terminus to the central domain. Our findings revealed that Nsp1 has a versatile C-terminus region which changes its conformations with respect to its host binding partner. Identified novel binding sites within the Nsp1 can assist in understanding its networking (in current or future such infections), as well as support drug discovery programs aimed at targeting the coronavirus family.<\/jats:p>","DOI":"10.1007\/s00249-025-01762-y","type":"journal-article","created":{"date-parts":[[2025,6,14]],"date-time":"2025-06-14T14:43:37Z","timestamp":1749912217000},"page":"41-54","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Structural adaptability of SARS-CoV-2 Nsp1 with the host network"],"prefix":"10.1007","volume":"55","author":[{"given":"Monikaben","family":"Padariya","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ted","family":"Hupp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7757-6962","authenticated-orcid":false,"given":"Umesh","family":"Kalathiya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,6,14]]},"reference":[{"key":"1762_CR1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0251834","volume":"16","author":"T Agback","year":"2021","unstructured":"Agback T, Dominguez F, Frolov I, Frolova EI, Agback P (2021) 1H, 13C and 15N resonance assignment of the SARS-CoV-2 full-length nsp1 protein and its mutants reveals its unique secondary structure features in solution. 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