6C0O

Crystal structure of HIV-1 K103N mutant reverse transcriptase in complex with non-nucleoside inhibitor 25a

Summary for 6C0O

• Entry DOI: 10.2210/pdb6c0o/pdb
• Related: 6C0J 6C0K 6C0L 6C0N
• Descriptor: Reverse transcriptase/ribonuclease H, Reverse transcriptase p51 subunit, 4-({4-[(4-{4-[(E)-2-cyanoethenyl]-2,6-dimethylphenoxy}thieno[3,2-d]pyrimidin-2-yl)amino]piperidin-1-yl}methyl)benzene-1-sulfonamide, ... (8 entities in total)
• Functional Keywords: non-nucleoside inhibitor, replication
• Biological source: Human immunodeficiency virus type 1 group M subtype B (isolate BH10); More
• Total number of polymer chains: 2
• Total formula weight: 116520.39

Authors

Yang, Y.,Nguyen, L.A.,Smithline, Z.B.,Steitz, T.A. (deposition date: 2018-01-01, release date: 2018-08-01, Last modification date: 2023-10-04)

Primary citation

Yang, Y.,Kang, D.,Nguyen, L.A.,Smithline, Z.B.,Pannecouque, C.,Zhan, P.,Liu, X.,Steitz, T.A.
Structural basis for potent and broad inhibition of HIV-1 RT by thiophene[3,2-d]pyrimidine non-nucleoside inhibitors.
Elife, 7:-, 2018

PubMed Abstract: Rapid generation of drug-resistant mutations in HIV-1 reverse transcriptase (RT), a prime target for anti-HIV therapy, poses a major impediment to effective anti-HIV treatment. Our previous efforts have led to the development of two novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) with piperidine-substituted thiophene[3,2-]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 Å 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.

PubMed: 30044217
DOI: 10.7554/eLife.36340

Experimental method

X-RAY DIFFRACTION (1.901 Å)