Comparison of ASV and HIV-1 Integrases

 Home Page National Cancer Institute Macromolecular Crystallography Laboratory Retroviral Integrase Project NCI-Frederick MCL - Protein Structure Section
Structures determined by the Macromolecular Crystallography Laboratory, Protein Structure Section at the NCI-Frederick campus. Work performed in collaboration with the Skalka Laboratory in the Institute for Cancer Research, Fox Chase Cancer Center, and HIV-1 IN work with Drs Qing and Clément-Mella of Rhone-Poulenc Rorer (France).





HIV IN (F185H)ASV IN


Catalytic core domains of HIV-1 IN next to ASV IN. The flexible loop, in the left foreground, is completely visible in several structures of ASV IN. Note that the length of this loop is identical in both proteins, and the sequence is very highly conserved (especially compared with other parts of the protein, which are not at all similar in amino acid sequence; see below).


ASV and HIV sequences compared


ASV IN and HIV-1 IN have a remarkably similar three-dimensional (3D) structure. This is not the case for their amino acid sequences. Only 24% of the sequences are identical (marked in black), with an additional 8% homology (amino acids with similar properties, marked in grey). Overall homology is 32%, although certain critical regions share a higher identity. Note especially the high degree of identity around the active site residues (ASV#/HIV#), D64/D64, D121/D116, E157/E152 and the flexible loop region 139-153/134-152. Open bars below the sequences show the location of (alpha) helices, represented in the top image as brown or yellow spirals. Black arrows show the location of (beta) strands, represented in the top image as blue or green bands. Directions of the arrowheads in the colored ribbon diagram and the sequence correspond. Note how the sequence and the 3D structure correspond in these images. *Sequence diagram adapted from work done for the MSL by Richard Frederickson, Publications Dept., NCI-FCRDC.

The active form for IN in vivo (in the cell) is still not known. At the very least, a dimer must be present. Some evidence suggests a tetramer (two dimers) is required for IN to have full activity, but this is not conclusive. The image to the left is the crystallographic dimer.

This image shows the catalytic core domain of ASV IN overlaid upon that of HIV-1 IN. The structures are very similar in regard to individual molecules (monomers) shown here with ASV IN in blue and HIV-1 IN in yellow. Interaction between two HIV-1 IN monomers (yellow, red) or two ASV IN monomers (blue, green) to form a functional unit shows more differences (note the overlay of red, green) in the dimer structures. *Image courtesy of Dr. Mariusz Jaskólski, Center for Biocrystallographic Research.


The Macromolecular Structure Laboratory has solved the structure of the F185H construct of the HIV-1 IN catalytic domain. This mutation increases the solubility of the core domain without affecting function. The first published structure of HIV-1 IN was with the F185K mutation, which did not show a complete model for the flexible loop. Although the complete loop has been reported for a structure of HIV-1 IN F185K, as yet this structure has not been published.

The coordinate and image files of HIV IN F185H are available from the PDB.

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contact: Jerry N. Alexandratos at alexandr@ncifcrf.gov.