3LPU

HIV integrase

Summary for 3LPU

• Entry DOI: 10.2210/pdb3lpu/pdb
• Related: 1HYV 3LPT
• Descriptor: Integrase, (2S)-2-(6-chloro-2-methyl-4-phenylquinolin-3-yl)pentanoic acid, 2-[3-[3-(2-hydroxyethoxy)propoxy]propoxy]ethanol, ... (7 entities in total)
• Functional Keywords: hiv, integrase, ledgf/p75 small molecule, inhibitor, endonuclease, hydrolase, nuclease, transferase, viral protein
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 1
• Total formula weight: 19551.35

Authors

Nicolet, S.,Christ, F.,Voet, A.,Marchand, A.,Strelkov, S.V.,de Maeyer, M.,Chaltin, P.,Debyzer, Z. (deposition date: 2010-02-06, release date: 2010-05-12, Last modification date: 2024-11-13)

Primary citation

Christ, F.,Voet, A.,Marchand, A.,Nicolet, S.,Desimmie, B.A.,Marchand, D.,Bardiot, D.,Van der Veken, N.J.,Van Remoortel, B.,Strelkov, S.V.,De Maeyer, M.,Chaltin, P.,Debyser, Z.
Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication.
Nat.Chem.Biol., 6:442-448, 2010

PubMed Abstract: Lens epithelium-derived growth factor (LEDGF/p75) is a cellular cofactor of HIV-1 integrase that promotes viral integration by tethering the preintegration complex to the chromatin. By virtue of its crucial role in the early steps of HIV replication, the interaction between LEDGF/p75 and integrase represents an attractive target for antiviral therapy. We have rationally designed a series of 2-(quinolin-3-yl)acetic acid derivatives (LEDGINs) that act as potent inhibitors of the LEDGF/p75-integrase interaction and HIV-1 replication at submicromolar concentration by blocking the integration step. A 1.84-A resolution crystal structure corroborates the binding of the inhibitor in the LEDGF/p75-binding pocket of integrase. Together with the lack of cross-resistance with two clinical integrase inhibitors, these findings define the 2-(quinolin-3-yl)acetic acid derivatives as the first genuine allosteric HIV-1 integrase inhibitors. Our work demonstrates the feasibility of rational design of small molecules inhibiting the protein-protein interaction between a viral protein and a cellular host factor.

PubMed: 20473303
DOI: 10.1038/nchembio.370

Experimental method

X-RAY DIFFRACTION (1.95 Å)