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Our previous efforts have led to the development of two novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) with piperidine-substituted thiophene[3,2-d]pyrimidine scaffolds, compounds K-5a2 and 25a, which demonstrate highly potent anti-HIV-1 activities and improved resistance profiles compared with etravirine and rilpivirine, respectively. Here, we have determined the crystal structures of HIV-1 wild-type (WT) RT and seven RT variants bearing prevalent drug-resistant mutations in complex with K-5a2 or 25a at ~2 \u00c5 resolution. These high-resolution structures illustrate the molecular details of the extensive hydrophobic interactions and the network of main chain hydrogen bonds formed between the NNRTIs and the RT inhibitor-binding pocket, and provide valuable insights into the favorable structural features that can be employed for designing NNRTIs that are broadly active against drug-resistant HIV-1 variants.<\/jats:p>","DOI":"10.7554\/elife.36340","type":"journal-article","created":{"date-parts":[[2018,7,25]],"date-time":"2018-07-25T08:00:25Z","timestamp":1532505625000},"source":"Crossref","is-referenced-by-count":73,"title":["Structural basis for potent and broad inhibition of HIV-1 RT by thiophene[3,2-d]pyrimidine non-nucleoside inhibitors"],"prefix":"10.7554","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9061-3828","authenticated-orcid":true,"given":"Yang","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Molecular Biophysics and Biochemistry, Yale University, New 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