title: Crystal structure of tert-butyldimethylsilyl-spiroaminooxathioledioxide-thymine (TSAO-T) in complex with HIV-1 reverse transcriptase (RT) redefines the elastic limits of the non-nucleoside inhibitor-binding pocket.
abstract: tert-Butyldimethylsilyl-spiroaminooxathioledioxide (TSAO) compounds have an embedded thymidine-analogue backbone; however, TSAO compounds invoke non-nucleoside RT inhibitor (NNRTI) resistance mutations. Our crystal structure of RT:7 (TSAO-T) complex shows that 7 binds inside the NNRTI-binding pocket, assuming a "dragon" shape, and interacts extensively with almost all the pocket residues. The structure also explains the structure-activity relationships and resistance data for TSAO compounds. The binding of 7 causes hyper-expansion of the pocket and significant rearrangement of RT subdomains. This nonoptimal complex formation is apparently responsible (1) for the lower stability of a RT (p66/p51) dimer and (2) for the lower potency of 7 despite of its extensive interactions with RT. However, the HIV-1 RT:7 structure reveals novel design features such as (1) interactions with the conserved Tyr183 from the YMDD-motif and (2) a possible way for an NNRTI to reach the polymerase active site that may be exploited in designing new NNRTIs.
authors: Center for Advanced Biotechnology and Medicine (CABM), Rutgers University, Piscataway, New Jersey 08854, United States. kalyan@cabm.rutgers.edu
authors: Kalyan
authors: K
authors: Das
authors: Joseph D
authors: JD
authors: Bauman
authors: Angela S
authors: AS
authors: Rim
authors: Chhaya
authors: C
authors: Dharia
authors: Arthur D
authors: AD
authors: Clark
authors: María-José
authors: MJ
authors: Camarasa
authors: Jan
authors: J
authors: Balzarini
authors: Eddy
authors: E
authors: Arnold
mesh_terms: D018360:Crystallography, X-Ray; D004548:Elasticity; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D013141:Spiro Compounds / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000031:analogs & derivatives* / Q000737:chemistry; D014529:Uridine / Q000031:analogs & derivatives
chemical_list: D018894:Reverse Transcriptase Inhibitors; D013141:Spiro Compounds; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D013936:Thymidine; C075132:TSAO-T; D014529:Uridine