{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T14:53:08Z","timestamp":1761058388322},"reference-count":51,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2006,1,1]],"date-time":"2006-01-01T00:00:00Z","timestamp":1136073600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2006,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Molecular modeling studies have identified a putative human immunodeficiency virus (HIV) integrase (IN) inhibitor-binding pocket for\n            <jats:sc>l<\/jats:sc>\n            -chicoric acid (\n            <jats:sc>l<\/jats:sc>\n            -CA) and other inhibitors of IN (C. A. Sotriffer, H. Ni, and A. McCammon, J. Med. Chem. 43:4109-4117, 2000). By using site-directed mutagenesis of several amino acid residues identified by modeling studies, a common inhibitor-binding pocket on IN was confirmed for\n            <jats:sc>l<\/jats:sc>\n            -CA and the diketo acid L-731,988. Specifically, the single mutations E92K, Q148A, K156A, K156R, G140S, and G149S, as well as the double mutations C65S-K156N and H67D-G140A were evaluated for their effects on enzymatic activity and inhibitor susceptibility. Each recombinant IN was attenuated for 3\u2032-end processing and strand transfer activities. Most proteins were also attenuated for disintegration; the IN that contained K156R and C65S-K156N, however, displayed disintegration activity similar to that of IN from HIV\n            <jats:sub>NL4-3<\/jats:sub>\n            . All mutant IN proteins demonstrated decreased susceptibility to\n            <jats:sc>l<\/jats:sc>\n            -CA, while all mutant proteins except E92K and K156R demonstrated resistance to L-731,988. These data validate the computer modeling data and demonstrate that\n            <jats:sc>l<\/jats:sc>\n            -CA and L-731,988 share an overlapping inhibitor-binding pocket that involves amino acids Q148, C65, and H67. The resistance studies confirm that L-731,988 fills one-half of the inhibitor-binding pocket and binds to Q148 but excludes E92, while\n            <jats:sc>l<\/jats:sc>\n            -CA fills the entire binding groove and thus interacts with E92. These results provide \u201cwet laboratory\u201d evidence that molecular models of the HIV IN inhibitor-binding pocket can be used for drug discovery.\n          <\/jats:p>","DOI":"10.1128\/aac.50.1.134-142.2006","type":"journal-article","created":{"date-parts":[[2005,12,23]],"date-time":"2005-12-23T10:07:51Z","timestamp":1135332471000},"page":"134-142","update-policy":"http:\/\/dx.doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":24,"title":["Preliminary Mapping of a Putative Inhibitor-Binding Pocket for Human Immunodeficiency Virus Type 1 Integrase Inhibitors"],"prefix":"10.1128","volume":"50","author":[{"given":"Deborah J.","family":"Lee","sequence":"first","affiliation":[{"name":"Departments of Microbiology and Molecular Genetics"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"Jr.","given":"W. 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