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Nonetheless, the notorious insolubility of HBV RT has hindered experimental structural studies and structure-based drug design. Here, we demonstrate that a Q151M substitution alone at the nucleotide-binding site (N-site) of human immunodeficiency virus type-1 (HIV-1) RT renders HIV-1 highly sensitive to entecavir (ETV), a potent nucleoside analogue RT inhibitor (NRTI) against HBV. The results suggest that Met151 forms a transient hydrophobic interaction with the cyclopentyl methylene of ETV, a characteristic hydrophobic moiety of ETV. We thus solved the crystal structures of HIV-1 RT<jats:sup>Q151M<\/jats:sup>:DNA complex with bound dGTP or ETV-triphosphate (ETV-TP). The structures revealed that ETV-TP is accommodated at the N-site slightly apart from the ribose ring of the 3\u2032-end nucleotide, compared to the position of bound dGTP and previously reported NRTI\/dNTP. In addition, the protruding methylene group of bound ETV-TP directly pushes the side-chain of Met184 backward. Met184 is a key residue that confers ETV resistance upon substitution with smaller Ile\/Val. These results provide novel insights into NRTI binding to the N-site and further provide important clues for the development of novel anti-HBV\/HIV-1 RT inhibitors to overcome critical drug resistance.<\/jats:p>","DOI":"10.1038\/s41598-018-19602-9","type":"journal-article","created":{"date-parts":[[2018,1,22]],"date-time":"2018-01-22T09:50:23Z","timestamp":1516614623000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["HIV-1 with HBV-associated Q151M substitution in RT becomes highly susceptible to entecavir: structural insights into HBV-RT inhibition by entecavir"],"prefix":"10.1038","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4521-7516","authenticated-orcid":false,"given":"Yoshiaki","family":"Yasutake","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shin-ichiro","family":"Hattori","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hironori","family":"Hayashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kouki","family":"Matsuda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noriko","family":"Tamura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satoru","family":"Kohgo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenji","family":"Maeda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroaki","family":"Mitsuya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2018,1,26]]},"reference":[{"key":"19602_CR1","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1046\/j.1365-2893.2003.00487.x","volume":"11","author":"D Lavanchy","year":"2004","unstructured":"Lavanchy, D. 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