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Document Page 102 reaction is followed by DNA relaxation (unwinding, rotation, etc.), resulting in the site on the target DNA for the second transfer reaction site now being located close to the active site of the second monomer [42]. An alternate possibility is that a multimer larger than a dimer is responsible for the coordinated cutting and strand-transfer reactions. For example, two contacting dimers can be modeled such that two active sites of the resulting tetramer are located 15–20 Å apart. It is also possible that even higher order multimers are involved. There is, as yet, no convincing evidence in support of any one model. The observation that RSV integrase cuts target DNA with a six-base-pair stagger rather than the five observed for HIV correlates intriguingly with the apparently longer distance (~ 38 Å vs. 35 Å) between active sites in the RSV dimer. However, understanding the coordinated cutting and joining reaction awaits three-dimensional information on the arrangement of monomers within an integrase multimer binding to DNA. E. Three-Dimensional Structures of Other Domains of HIV-1 Integrase Three-dimensional structural information has not yet been obtained for a full-length integrase protein. In its absence, attempts have been made to determine the structure of the smaller domains consisting of the separately expressed N- and C-termini that flank the core whose structure is now known. The Amino Terminus of Integrase While the N-terminus of HIV-1 integrase, consisting of residues 1 to 55, has been separately expressed, purified, and biophysically characterized [31], structural data has not yet been obtained. This protein domain binds metal ions such as Zn 2+, Co 2+, and Cd 2+ stoichiometrically, and is monomeric at low protein concentrations. Dramatic changes in helix content (from 14% to 32%) are observed in the circular dichroism (CD) spectrum upon addition of metal. Analysis of CD spectral features led researchers to conclude that it is highly probably that integrase contains a zinc finger that folds in much the same way as the TFIIIA-like DNA binding proteins, with two His residues located on an α helix and two cysteines part of a β sheet [31]. However, confirmation of such a model awaits structure determination by x-ray crystallography or NMR spectroscopy. The Carboxy Terminus of Integrase When the C-terminal domain is expressed as a separate polypeptide, IN 213–288 can be purified from the initial soluble fraction from cell lysates [33]. This small protein fragment, therefore, was an attractive target for structure determination. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_102.html [4/5/2004 4:51:59 PM]
Document Figure 8 Molscript stereo figure of the structure of the nonspecific DNA-binding domain of HIV-1 integrase, IN 220–270 , determined by heteronuclear NMR spectroscopy [28]. Page 103 The structure of this domain is of particular interest as it represents the dominant nonspecific DNAbinding region of integrase. Gel filtration and sedimentation equilibrium results indicated that purified IN 213–288 partitioned between dimers and highly aggregated material (unpublished observations). However, a smaller domain consisting of residues 220 to 270 maintains the DNA-binding properties of the longer C-terminal domain and is better behaved in solution. Recently, two groups have reported the structure of this smaller fragment, IN 220–270, determined using multidimensional heteronuclear NMR spectroscopic methods [28,29]. As shown in Figure 8, the overall structure of IN 220–270, is that of a β sandwich formed by two threestranded β sheets. As anticipated by biophysical studies, the polypeptide is a dimer in solution. The interface between monomers is formed by the antiparallel interaction of three β strands from each subunit and is stabilized predominantly by hydrophobic interactions. There is a long loop between strands β1 and β2 which, in the dimer, defines the sides of a cleft that is of the appropriate dimensions (about 24 × 24 × 12 Å) to accommodate double-stranded DNA. The folding topology is very similar to that of SH3 domains that are found in several proteins involved in signal transduction, despite the lack of significant sequence homology. This is rather unusual since SH3 domains are generally involved in protein binding rather than interactions with DNA. V. Prospects for Inhibitors A. Overview of Inhibitor Studies to Date The investigation of HIV integrase inhibitors has been largely restricted to testing available compounds that inhibit other enzymes with similar substrates or http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_103.html (1 of 2) [4/5/2004 4:52:07 PM]
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Page 85 and 86: Document Chris Tantillo. The work i
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Page 103 and 104: Document dine) and didanosine (dide
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Page 149 and 150: Document 4 Bradykinin Receptor Anta
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