An unusual helix turn helix motif in the catalytic core of HIV-1 integrase binds viral DNA and LEDGF.

PloS One
Hayate MeradSerge Fermandjian

Abstract

Integrase (IN) of the type 1 human immunodeficiency virus (HIV-1) catalyzes the integration of viral DNA into host cellular DNA. We identified a bi-helix motif (residues 149-186) in the crystal structure of the catalytic core (CC) of the IN-Phe185Lys variant that consists of the alpha(4) and alpha(5) helices connected by a 3 to 5-residue turn. The motif is embedded in a large array of interactions that stabilize the monomer and the dimer. We describe the conformational and binding properties of the corresponding synthetic peptide. This displays features of the protein motif structure thanks to the mutual intramolecular interactions of the alpha(4) and alpha(5) helices that maintain the fold. The main properties are the binding to: 1- the processing-attachment site at the LTR (long terminal repeat) ends of virus DNA with a K(d) (dissociation constant) in the sub-micromolar range; 2- the whole IN enzyme; and 3- the IN binding domain (IBD) but not the IBD-Asp366Asn variant of LEDGF (lens epidermal derived growth factor) lacking the essential Asp366 residue. In our motif, in contrast to the conventional HTH (helix-turn-helix), it is the N terminal helix (alpha(4)) which has the role of DNA recognition helix, while the C terminal he...Continue Reading

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Methods Mentioned

BETA
X-ray
NMR
circular dichroism
Fluorescence

Software Mentioned

GOR IV
GOR
PyMol
Insight
AGADIR

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