7OZ5
Crystal structure of HIV-1 reverse transcriptase with a double stranded DNA in complex with fragment 166 at the transient P-pocket.
Summary for 7OZ5
| Entry DOI | 10.2210/pdb7oz5/pdb |
| Related | 7OXQ 7OZ2 |
| Related PRD ID | PRD_900003 |
| Descriptor | Reverse transcriptase/ribonuclease H, Gag-Pol polyprotein, DNA (28-MER), ... (8 entities in total) |
| Functional Keywords | reverse transcriptase, rt-dna complex, rt sliding, transferase-dna complex, p-1 complex, p51, p66, transferase |
| Biological source | Human immunodeficiency virus type 1 group M subtype B (isolate BH10) (HIV-1) More |
| Total number of polymer chains | 8 |
| Total formula weight | 265079.72 |
| Authors | Martinez, S.E.,Singh, A.K.,Das, K. (deposition date: 2021-06-25, release date: 2021-12-08, Last modification date: 2024-01-31) |
| Primary citation | Singh, A.K.,Martinez, S.E.,Gu, W.,Nguyen, H.,Schols, D.,Herdewijn, P.,De Jonghe, S.,Das, K. Sliding of HIV-1 reverse transcriptase over DNA creates a transient P pocket - targeting P-pocket by fragment screening. Nat Commun, 12:7127-7127, 2021 Cited by PubMed Abstract: HIV-1 reverse transcriptase (RT) slides over an RNA/DNA or dsDNA substrate while copying the viral RNA to a proviral DNA. We report a crystal structure of RT/dsDNA complex in which RT overstepped the primer 3'-end of a dsDNA substrate and created a transient P-pocket at the priming site. We performed a high-throughput screening of 300 drug-like fragments by X-ray crystallography that identifies two leads that bind the P-pocket, which is composed of structural elements from polymerase active site, primer grip, and template-primer that are resilient to drug-resistance mutations. Analogs of a fragment were synthesized, two of which show noticeable RT inhibition. An engineered RT/DNA aptamer complex could trap the transient P-pocket in solution, and structures of the RT/DNA complex were determined in the presence of an inhibitory fragment. A synthesized analog bound at P-pocket is further analyzed by single-particle cryo-EM. Identification of the P-pocket within HIV RT and the developed structure-based platform provide an opportunity for the design new types of polymerase inhibitors. PubMed: 34880240DOI: 10.1038/s41467-021-27409-y PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.37 Å) |
Structure validation
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