4E7L: Pfv Integrase Strand Transfer Complex (Stc-Mn) Following Reaction In Crystallo, At 3.0 A Resolution

Citation:
Abstract
Retroviral integrase (IN) is responsible for two consecutive reactions, which lead to insertion of a viral DNA copy into a host cell chromosome. Initially, the enzyme removes di- or trinucleotides from viral DNA ends to expose 3'-hydroxyls attached to the invariant CA dinucleotides (3'-processing reaction). Second, it inserts the processed 3'-viral DNA ends into host chromosomal DNA (strand transfer). Herein, we report a crystal structure of prototype foamy virus IN bound to viral DNA prior to 3'-processing. Furthermore, taking advantage of its dependence on divalent metal ion cofactors, we were able to freeze trap the viral enzyme in its ground states containing all the components necessary for 3'-processing or strand transfer. Our results shed light on the mechanics of retroviral DNA integration and explain why HIV IN strand transfer inhibitors are ineffective against the 3'-processing step of integration. The ground state structures moreover highlight a striking substrate mimicry utilized by the inhibitors in their binding to the IN active site and suggest ways to improve upon this clinically relevant class of small molecules.
PDB ID: 4E7LDownload
MMDB ID: 99931
PDB Deposition Date: 2012/3/17
Updated in MMDB: 2012/08
Experimental Method:
x-ray diffraction
Resolution: 3  Å
Source Organism:
synthetic construct
Similar Structures:
Biological Unit for 4E7L: dodecameric; determined by author and by software (PISA)
Molecular Components in 4E7L
Label Count Molecule
Proteins (4 molecules)
4
Pro-pol Polyprotein
Molecule annotation
Nucleotides(4 molecules)
2
DNA (5'- D(*ap*tp*tp*gp*tp*cp*ap*tp*gp*gp*ap*ap*tp*tp*tp*cp*gp*cp*a)-3')
Molecule annotation
2
DNA (5'- D(tpgpcpgpapapaptptpcpcpaptpgpapcpa)-3')
Molecule annotation
2
DNA (5'-d(*cp*cp*cp*gp*ap*gp*gp*cp*ap*cp*gp*tp*g)-3')
Molecule annotation
2
DNA (5'- D(pcptpapgpcpapcpgptpgpcpcptpcpgpgpg)-3')
Molecule annotation
Chemicals (10 molecules)
1
2
2
6
3
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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