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Document well folded since it is relatively resistant to proteolysis. As it is also active for disintegration, we concluded that it contained the enzyme active site. Page 93 We exploited the convenience of histidine-tag (HT) technology to develop methods to purify large quantities of IN 50–212 [12]. A 20-amino-acid histidine-containing tag was added to the N-terminus of HIV-1 IN 50–212 [22] to allow rapid purification on nickel affinity columns. It was subsequently removed by thrombin cleavage. Biophysical studies showed that although buffer conditions could be identified where the protein was soluble to ~ 4 mg/mL, under these conditions the protein was highly aggregated (unpublished observations). Although the aggregation problem could be largely avoided by the addition of high concentrations of the zwitterionic detergent CHAPS, conditions could not be identified under which protein crystals formed in the presence of CHAPS. D. Systematic Mutation of Hydrophobic Residues to Improve Protein Solubility As it became clear that IN 50–212 was crystallographically challenged, a condition readily understood in terms of its aggregation problems and low solubility, a more radical approach was undertaken to try and improve its biophysical properties. Hydrophobic residues in the catalytic core were targeted for sitespecific mutation according to the following criteria: where two or more hydrophobic residues were encountered close together in the primary amino acid sequence, they were each changed to an alanine residue. When a hydrophobic residue stood alone, it was mutated to lysine. In this way, 29 different mutant proteins of IN 50–212 were rapidly generated using the overlapping polymerase chain reaction (PCR) and screened for improved solubility properties [34]. Three mutated proteins were identified that were more soluble at lower NaCl concentration than the unmutated core (V165K, F185K, and the double mutation of W131A/W132A). However, one of these in which Phe185 was mutated to Lys had dramatically improved solubility and was ultimately crystallized and its three-dimensional structure determined [3]. The remarkable biophysical properties of this single point mutant of IN 50–212 have recently been described [34]. IV. Structure Of The Catalytic Core Domain Of HIV-1 Integrase A. Description of the Structure The Overall Protein Fold The three-dimensional structure of the catalytic core domain of HIV-1 integrase is centered on a mixed five stranded β sheet flanked by several helices forming http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_93.html [4/5/2004 4:55:17 PM]
Document Figure 6 Molscript stereo figure of the three-dimensional structure of the catalytic core of HIV-1 integrase. The two catalytically essential aspartic acid residues (D64 and D116) visible in the x-ray structure are highlighted. Page 94 an α-β meander sandwich (see Figure 6) [35]. In the crystal structure, interpretable electron density starts at Cys56, leading to a short loop. The first β strand starts at Gly59 and runs until Val68. The two central residues of a type I' reverse β turn, Glu69 and Gly70, change the polypeptide chain direction to form the second β strand between residues Lys71 and His78, which runs antiparallel with the first strand. A type I'β turn follows, with Val79 and Ala80 changing the chain direction again to form the third β strand between Ser81 and Ile89, which runs antiparallel with the second strand. A short loop between Pro90 and Glu92 leads to the first α helix (helix A) between Thr93 and Trp108. This helix packs against the bottom face of the sheet formed by the first three antiparallel strands by several hydrophobic interactions. A short loop (Pro109 and Val110) leads to the fourth β strand between Lys111 and His114. This strand is parallel with the first. A short loop starting at Thr115 leads to helix B, a one turn helix between Gly118 and Thr122, followed by helix C between Ser123 and Ala133. This helix runs parallel to and packs against helix A. The residues Gly134 and Ile135 form a short loop prior to the fifth and last β strand of the structure between Lys136 and Ala138. This short strand is parallel with the first and the fourth. There is no interpretable electron density due to disorder between Gly140 and Met154. At Met154, the fourth α helix (helix D) starts and runs until Ala169 on the top face of the sheet formed by the first three β strands. The residue Glu170 leads into the next helix (helix E) running between His171 and Lys186, the first residue of a short basic sequence (Lys186, Arg187, and Lys188). Together with http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_94.html (1 of 2) [4/5/2004 4:55:35 PM]
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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 99 and 100: Document 106. Cirino NM, Cameron CE
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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 D ddI, 152 tumour necrosis
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Document antistasin peptides, 281 c
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