Summary information and primary citation
- PDB-id
- 4be1; SNAP-derived features in text and JSON formats;
DNAproDB
- Class
- transferase-DNA
- Method
- X-ray (2.71 Å)
- Summary
- Pfv intasome with inhibitor xz-116
- Reference
- Metifiot M, Maddali K, Johnson BC, Hare S, Smith SJ, Zhao XZ, Marchand C, Burke TR, Hughes SH, Cherepanov P, Pommier Y (2013): "Activities, Crystal Structures and Molecular Dynamics of Dihydro-1H-Isoindole Derivatives, Inhibitors of HIV-1 Integrase." Acs Chem.Biol., 8, 209. doi: 10.1021/CB300471N.
- Abstract
- On the basis of a series of lactam and phthalimide derivatives that inhibit HIV-1 integrase, we developed a new molecule, XZ-259, with biochemical and antiviral activities comparable to raltegravir. We determined the crystal structures of XZ-259 and four other derivatives in complex with the prototype foamy virus intasome. The compounds bind at the integrase-Mg(2+)-DNA interface of the integrase active site. In biochemical and antiviral assays, XZ-259 inhibits raltegravir-resistant HIV-1 integrases harboring the Y143R mutation. Molecular modeling is also presented suggesting that XZ-259 can bind in the HIV-1 intasome with its dimethyl sulfonamide group adopting two opposite orientations. Molecular dynamics analyses of the HIV-1 intasome highlight the importance of the viral DNA in drug potency.
