3LPT: HIV integrase

Citation:
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.
PDB ID: 3LPTDownload
MMDB ID: 82019
PDB Deposition Date: 2010/2/5
Updated in MMDB: 2015/12
Experimental Method:
x-ray diffraction
Resolution: 2  Å
Source Organism:
Similar Structures:
Biological Unit for 3LPT: dimeric; determined by author and by software (PISA)
Molecular Components in 3LPT
Label Count Molecule
Proteins (2 molecules)
2
Integrase
Molecule annotation
Chemicals (22 molecules)
1
2
2
8
3
2
4
6
5
2
6
2
* Click molecule labels to explore molecular sequence information.

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