3QO9

Crystal structure of HIV-1 Reverse Transcriptase (RT) in complex with TSAO-T, a non-nucleoside RT inhibitor (NNRTI)

Summary for 3QO9

• Entry DOI: 10.2210/pdb3qo9/pdb
• Related: 2ZD1 3DLK
• Descriptor: Reverse transcriptase/ ribonuclease H, p51 RT, 1-[(5R,6R,8R,9R)-4-amino-9-{[tert-butyl(dimethyl)silyl]oxy}-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dioxido-1,7-dioxa-2-thiaspiro[4.4]non-3-en-8-yl]-5-methylpyrimidine-2,4(1H,3H)-dione, ... (4 entities in total)
• Functional Keywords: aids, hiv, rna-binding, rna-directed dna polymerase, transferase, viral nucleoprotein, nonnucleoside, nnrti, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Human immunodeficiency virus type 1 BH10 (HIV-1); More
• Cellular location: Matrix protein p17: Virion (Potential). Capsid protein p24: Virion (Potential). Nucleocapsid protein p7: Virion (Potential). Reverse transcriptase/ribonuclease H: Virion (Potential). Integrase: Virion (Potential): P03366 P03366
• Total number of polymer chains: 2
• Total formula weight: 114674.69

Authors

Das, K.,Arnold, E. (deposition date: 2011-02-09, release date: 2011-05-04, Last modification date: 2023-09-13)

Primary citation

Das, K.,Bauman, J.D.,Rim, A.S.,Dharia, C.,Clark, A.D.,Camarasa, M.J.,Balzarini, J.,Arnold, E.
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.
J.Med.Chem., 54:2727-2737, 2011

PubMed 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.

PubMed: 21446702
DOI: 10.1021/jm101536x

Experimental method

X-RAY DIFFRACTION (2.6 Å)