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Document Gly193 and Tyr194, Lys188 and Gly189 form two short antiparallel β strands separated <strong>by</strong> a turn of three residues (Gly190, Ile191, and Gly192) not involved in main chain hydrogen bonds. The first residue of the last helix, (helix F), which runs until Asp212, is Ser194. Three Conserved Acidic Residues at the Enzyme Active Site Page 95 There are four amino acids in the core domain sequence that are absolutely conserved among retroviral integrases: Asp64, Asp116, Glu152, and Lys159. The three acidic residues form the conserved D,D-35- E motif and have been shown to be essential for catalysis (see Section III.A). The role of Lys159 in retroviral integrases is not obvious; its replacement with Val does not abolish catalytic activity, although there is a decrease in strand transfer activity [20]. The first essential acidic residue, Asp64, is located in the middle of the first β strand, while Asp116 is in a loop region right after the fourth β strand. These two residues define the active-site area and they are right next to each other three-dimensionally with their α-carbons separated <strong>by</strong> only 6.7 Å. The closest approach is 3.4 Å between Oδ1 of Asp64 and Cβ of Asp116. These residues are on the surface of the molecule, not part of any obvious substrate-binding cleft. The third catalytically essential acidic residue, Glu152, is in the disordered and hence crystallographically invisible region between Gly140 and Met154. Its location therefore must be inferred from other parts of the structure and from available threedimensional structures of related proteins. The location of Met154, the residue only two positions upstream from Glu152, is known because of interpretable electron density. The distance between the αcarbons of Glu152 and Met154 cannot be larger than about 7.3 Å, which constrains Glu152 to the neighborhood of the two other essential carboxylates, allowing it to contribute to the formation of a divalent metal-binding site. More recently, a crystal structure of the avian sarcoma virus (ASV) integrase core domain was solved [36]. Within this domain, ASV integrase has 24% sequence identity to the HIV-1 integrase core and, as expected, its three-dimensional structure is remarkably similar. The ASV integrase core in its native form has much better solution properties than the HIV-1 integrase core, and did not require any point mutations to render it crystallizable. Due to this fact and perhaps also due to its different crystal packing interactions, the crystal lattice of the ASV integrase core domain is somewhat more ordered than that of HIV-1. The two three-dimensional structures can be aligned quite well, using 74 α-carbons, with an rms deviation of only 1.4 Å in these α-carbon positions. The most remarkable difference between the two structures is that in the ASV structure the electron density is interpretable in all parts of the molecule. This is not to say, however, that serious disorder is not present. For example, in one particular loop, the temperature factors are above 70 Å 2 for the α carbons, indicating larger than 1 Å mean displacement value for these atoms. The corresponding http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_95.html [4/5/2004 4:55:37 PM]
Document Page 96 region in the HIV-1 structure is the uninterpretable stretch from residues 140 to 153, showing that beyond the three-dimensional similarity, the molecules also share a similar disorder pattern despite their different crystal packing interactions. It is clear that in the apoenzyme (metal-free) form of the HIV-1 integrase core, disorder is present in parts of the active site. However, in the holo form, structural stability must be necessary to form a metal-binding site. Position of the Third Essential Carboxylate Does the structure of ASV integrase give us a hint about the likely conformation of the polypeptide chain around Glu152 in the holoenzyme form of the HIV-1 integrase core? The answer is probably yes, considering the overall similarity of the structures. The first residue after the disordered part in the HIV- 1 integrase core is Met154, which is also the first residue in helix C. The corresponding helix in the ASV core is longer, running between Gln153 and Gly175. The residue analogous to Glu152 is Glu157 in the ASV integrase core structure, located a half-turn upstream from Ala159, which corresponds to Met154 in the HIV-1 integrase structure. It is plausible to assume, therefore, that the polypeptide chain in the holoenzyme form of HIV-1 integrase would also be in a helical conformation around Glu152, and its location would be very close to the one that can be inferred from the location of Glu157 in the ASV integrase core. Secondary structure prediction also supports this assumption, assigning α-helical structure around Glu152. Why does this helical turn show significant disorder in the HIV-1 integrase structure? The answer might be found in the amino acid sequence: Pro145 is a highly conserved residue among retroviral integrases, the only exception being ASV integrase where it is substituted with a Ser. Since the main chain nitrogen of a proline is not capable of participating in hydrogen bonding, it is very rarely found in helices. It is likely that if the polypeptide chain around Glu152 were helical in the holoenzyme form of the HIV-1 integrase core, then this helix would start after Pro145. There is no such restriction in the ASV integrase core, and it is possible that this is why helix C is longer in ASV than in HIV. This may also explain the disorder around Glu152 in the HIV-1 integrase core, since it is closer to the end of the helix and more susceptible to disordering effects. A longer helix and therefore a more ordered active site in the apo form may be a unique feature of the ASV integrase core. B. Similarity to Other Polynucleotidyl Transferases Overall Protein Folds The catalytic core domain of HIV-1 integrase has a topologically identical fold with the RNase H domain of HIV-1 reverse transcriptase [37], the RuvC Holli- http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_96.html [4/5/2004 4:55:39 PM]
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Structure-based Drug Design 14 Stru
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Document Page 54 Table 2) [12,54].
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Page 81 and 82: Document Page 67 Biochemical data s
Page 83 and 84: Document Page 69 determining the me
Page 85 and 86: Document Chris Tantillo. The work i
Page 87 and 88: Document Page 72 16. Goldman ME, Nu
Page 89 and 90: Document 30. Coffin JM. HIV populat
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Page 93 and 94: Document reverse transcriptase inhi
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Page 101 and 102: Document 122. Marshall WS, Beaton G
Page 103 and 104: Document dine) and didanosine (dide
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Page 107 and 108: Document 163. Lacey SF, Larder BA.
Page 109 and 110: Document Figure 1 Retroviral lifecy
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Page 113 and 114: Document Page 88 transfer (Figure 3
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Page 137 and 138: Document when metals are bound. Fin
Page 139 and 140: Document cubation of phosphotyrosin
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Page 149 and 150: Document 4 Bradykinin Receptor Anta
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Document antistasin peptides, 281 c
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Document Kininogen, 119 high molecu
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Document RT inhibitor, 41, 56 Nonpe
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Document Phosphoglycerate kinase (P
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Document [Protease targets] serinyl
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