Small-Molecule CD4 Mimics Interact with a Highly Conserved Pocket on HIV-1 gp120
Human immunodeficiency virus (HIV-1) interaction with the primary receptor, CD4, induces conformational changes in the viral envelope glycoproteins that allow binding to the CCR5 second receptor and virus entry into the host cell. The small molecule NBD-556 mimics CD4 by binding the gp120 exterior e...
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| Veröffentlicht in: | Structure (London) 2008-11, Vol.16 (11), p.1689-1701 |
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| creator | Madani, Navid Schön, Arne Princiotto, Amy M. LaLonde, Judith M. Courter, Joel R. Soeta, Takahiro Ng, Danny Wang, Liping Brower, Evan T. Xiang, Shi-Hua Do Kwon, Young Huang, Chih-chin Wyatt, Richard Kwong, Peter D. Freire, Ernesto Smith, Amos B. Sodroski, Joseph |
| description | Human immunodeficiency virus (HIV-1) interaction with the primary receptor, CD4, induces conformational changes in the viral envelope glycoproteins that allow binding to the CCR5 second receptor and virus entry into the host cell. The small molecule NBD-556 mimics CD4 by binding the gp120 exterior envelope glycoprotein, moderately inhibiting virus entry into CD4-expressing target cells and enhancing CCR5 binding and virus entry into CCR5-expressing cells lacking CD4. Studies of NBD-556 analogs and gp120 mutants suggest that (1) NBD-556 binds within the Phe 43 cavity, a highly conserved, functionally important pocket formed as gp120 assumes the CD4-bound conformation; (2) the NBD-556 phenyl ring projects into the Phe 43 cavity; (3) enhancement of CD4-independent infection by NBD-556 requires the induction of conformational changes in gp120; and (4) increased affinity of NBD-556 analogs for gp120 improves antiviral potency during infection of CD4-expressing cells. |
| doi_str_mv | 10.1016/j.str.2008.09.005 |
| format | Article |
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Studies of NBD-556 analogs and gp120 mutants suggest that (1) NBD-556 binds within the Phe 43 cavity, a highly conserved, functionally important pocket formed as gp120 assumes the CD4-bound conformation; (2) the NBD-556 phenyl ring projects into the Phe 43 cavity; (3) enhancement of CD4-independent infection by NBD-556 requires the induction of conformational changes in gp120; and (4) increased affinity of NBD-556 analogs for gp120 improves antiviral potency during infection of CD4-expressing cells.</description><identifier>ISSN: 0969-2126</identifier><identifier>EISSN: 1878-4186</identifier><identifier>DOI: 10.1016/j.str.2008.09.005</identifier><identifier>PMID: 19000821</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Acquired Immunodeficiency Syndrome - virology ; Calorimetry ; CD4 Antigens - chemistry ; CD4 Antigens - physiology ; Conserved Sequence ; HIV Envelope Protein gp120 - chemistry ; HIV-1 - chemistry ; HIV-1 - pathogenicity ; HIV-1 - physiology ; Human immunodeficiency virus 1 ; Humans ; MICROBIO ; Models, Molecular ; MOLIMMUNO ; Phenylalanine - chemistry ; Protein Conformation ; PROTEINS ; Receptors, CXCR4 - chemistry ; Recombinant Proteins - metabolism ; Thermodynamics</subject><ispartof>Structure (London), 2008-11, Vol.16 (11), p.1689-1701</ispartof><rights>2008 Elsevier Ltd</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c480t-4e7f3b52beaf4f30914c75ba2550e108f1404c1a5a4a06c1455002ef77a43a03</citedby><cites>FETCH-LOGICAL-c480t-4e7f3b52beaf4f30914c75ba2550e108f1404c1a5a4a06c1455002ef77a43a03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0969212608003675$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19000821$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Madani, Navid</creatorcontrib><creatorcontrib>Schön, Arne</creatorcontrib><creatorcontrib>Princiotto, Amy M.</creatorcontrib><creatorcontrib>LaLonde, Judith M.</creatorcontrib><creatorcontrib>Courter, Joel R.</creatorcontrib><creatorcontrib>Soeta, Takahiro</creatorcontrib><creatorcontrib>Ng, Danny</creatorcontrib><creatorcontrib>Wang, Liping</creatorcontrib><creatorcontrib>Brower, Evan T.</creatorcontrib><creatorcontrib>Xiang, Shi-Hua</creatorcontrib><creatorcontrib>Do Kwon, Young</creatorcontrib><creatorcontrib>Huang, Chih-chin</creatorcontrib><creatorcontrib>Wyatt, Richard</creatorcontrib><creatorcontrib>Kwong, Peter D.</creatorcontrib><creatorcontrib>Freire, Ernesto</creatorcontrib><creatorcontrib>Smith, Amos B.</creatorcontrib><creatorcontrib>Sodroski, Joseph</creatorcontrib><title>Small-Molecule CD4 Mimics Interact with a Highly Conserved Pocket on HIV-1 gp120</title><title>Structure (London)</title><addtitle>Structure</addtitle><description>Human immunodeficiency virus (HIV-1) interaction with the primary receptor, CD4, induces conformational changes in the viral envelope glycoproteins that allow binding to the CCR5 second receptor and virus entry into the host cell. 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The small molecule NBD-556 mimics CD4 by binding the gp120 exterior envelope glycoprotein, moderately inhibiting virus entry into CD4-expressing target cells and enhancing CCR5 binding and virus entry into CCR5-expressing cells lacking CD4. Studies of NBD-556 analogs and gp120 mutants suggest that (1) NBD-556 binds within the Phe 43 cavity, a highly conserved, functionally important pocket formed as gp120 assumes the CD4-bound conformation; (2) the NBD-556 phenyl ring projects into the Phe 43 cavity; (3) enhancement of CD4-independent infection by NBD-556 requires the induction of conformational changes in gp120; and (4) increased affinity of NBD-556 analogs for gp120 improves antiviral potency during infection of CD4-expressing cells.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>19000821</pmid><doi>10.1016/j.str.2008.09.005</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Cell Press Free Archives; Elsevier ScienceDirect Journals; EZB-FREE-00999 freely available EZB journals; Free Full-Text Journals in Chemistry |
| subjects | Acquired Immunodeficiency Syndrome - virology Calorimetry CD4 Antigens - chemistry CD4 Antigens - physiology Conserved Sequence HIV Envelope Protein gp120 - chemistry HIV-1 - chemistry HIV-1 - pathogenicity HIV-1 - physiology Human immunodeficiency virus 1 Humans MICROBIO Models, Molecular MOLIMMUNO Phenylalanine - chemistry Protein Conformation PROTEINS Receptors, CXCR4 - chemistry Recombinant Proteins - metabolism Thermodynamics |
| title | Small-Molecule CD4 Mimics Interact with a Highly Conserved Pocket on HIV-1 gp120 |
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