Summary
While the general features of HIV-1 integrase function are understood, there is still uncertainty about the composition of the integration complex and how integrase interacts with viral and host DNA. We propose an improved model of the integration complex based on current experimental evidence including a comparison with the homologous Tn5 transposase containing bound DNA and an analysis of DNA binding sites using Goodford’s GRID. Our model comprises a pair of integrase dimers, two strands of DNA to represent the viral DNA ends and a strand of bent DNA representing the host chromosome. In our model, the terminal four base pairs of each of the viral DNA strands interact with the integrase dimer providing the active site, while bases one turn away interact with a flexible loop (residues 186–194) on the second integrase dimer. We propose that residues E152, Q148 and K156 are involved in the specific recognition of the conserved CA dinucleotide and that the active site mobile loop (residues 140–149) stabilises the integration complex by acting as a barrier to separate the two viral DNA ends. In addition, the residues responsible for DNA binding in our model show a high level of amino acid conservation.
Similar content being viewed by others
References
Brown, P.O., In Retroviruses, Coffin J.M., Hughes S.H. and Varmus H.E. (Eds.), Integration, Cold Spring harbour Press, Plainview, NY, 1997, 161 pp.
P. Hindmarsh J. Leis (1999) Microbiol. Mol. Biol. Rev. 63 836 Occurrence Handle10585967
S.A. Chow (1997) Methods 12 306 Occurrence Handle10.1006/meth.1997.0484 Occurrence Handle9245611
T.S. Heuer P.O. Brown (1998) Biochemistry 37 6667 Occurrence Handle10.1021/bi972949c Occurrence Handle9578550
K. Gao S.L. Butler F. Bushman (2001) EMBO J. 20 3565 Occurrence Handle10.1093/emboj/20.13.3565 Occurrence Handle11432843
J.Y. Wang H. Ling W. Yang R. Craigie (2001) EMBO J. 20 7333 Occurrence Handle10.1093/emboj/20.24.7333 Occurrence Handle11743009
A.A. Podtelezhnikov K. Gao F.D. Bushman J.A. McCammon (2003) Biopolymers 68 110 Occurrence Handle10.1002/bip.10217 Occurrence Handle12579583
Z.N. Yang T.C. Mueser F.D. Bushman C.C. Hyde (2000) J. Mol. Biol. 296 535 Occurrence Handle10.1006/jmbi.1999.3463 Occurrence Handle10669607
Z. Chen Y. Yan S. Munshi Y. Li J. Zugay-Murphy B. Xu M. Witmer P. Felock A. Wolfe V. Sardana E.A. Emini D. Hazuda L.C. Kuo (2000) J. Mol. Biol. 296 521 Occurrence Handle10.1006/jmbi.1999.3451 Occurrence Handle10669606
J.C. Chen J. Krucinski L.J. Miercke J.S. Finer-Moore A.H. Tang A.D. Leavitt R.M. Stroud (2000) Proc. Natl. Acad. Sci. USA. 97 8233 Occurrence Handle10.1073/pnas.150220297 Occurrence Handle10890912
A.L. Perryman J.A. McCammon (2002) J. Med. Chem. 45 5624 Occurrence Handle10.1021/jm025554m Occurrence Handle12477345
L. De Luca A. Pedretti G. Vistoli M. Letizia Barreca L. Villa P. Monforte A. Chimirri (2003) Biochem. Biophys. Res. Commun. 310 1083 Occurrence Handle10.1016/j.bbrc.2003.09.120 Occurrence Handle14559226
T.K. Chiu D.R. Davies (2004) Curr. Top. Med. Chem. 4 965 Occurrence Handle10.2174/1568026043388547 Occurrence Handle15134551
C. Marchand A.A. Johnson R.G. Karki G.C. Pais X. Zhang K. Cowansage T.A. Patel M.C. Nicklaus T.R. Burke SuffixJr. Y. Pommier (2003) Mol. Pharmacol. 64 600 Occurrence Handle10.1124/mol.64.3.600 Occurrence Handle12920196
Bushman, F.D., Fujiwara, T., Craigie, R., Science (Washington, DC), 249 (1990) 1555.
F.D. Bushman R. Craigie (1991) Proc. Natl. Acad. Sci. USA. 88 1339 Occurrence Handle1847518
A. Engelman K. Mizuuchi R. Craigie (1991) Cell 67 1211 Occurrence Handle10.1016/0092-8674(91)90297-C Occurrence Handle1760846
A. Acel B.E. Udashkin M.A. Wainberg E.A. Faust (1998) J. Virol. 72 2062 Occurrence Handle9499061
E. Brin J. Yi A.M. Skalka J. Leis (2000) J.Biol. Chem. 275 39287 Occurrence Handle10.1074/jbc.M006929200 Occurrence Handle11006285
A. Engelman R. Craigie (1995) J. Virol. 69 5908 Occurrence Handle7637039
M.S. Hansen G.J. Smith T. Kafri V. Molteni J.S. Siegel F.D. Bushman (1999) Nat. Biotechnol. 17 578 Occurrence Handle10.1038/9886 Occurrence Handle10385323
Y. Hwang D. Rhodes F. Bushman (2000) Nucl. Acids Res. 28 4884 Occurrence Handle10.1093/nar/28.24.4884 Occurrence Handle11121479
S.A. Chow K.A. Vincent V. Ellison P.O. Brown (1992) Science (Washington, D.C.) 255 723
G. Bujacz M. Jaskoski J. Alexandratos A. Wlodawer G. Merkel R.A. Katz A.M. Skalka (1995) J. Mol. Biol. 253 333 Occurrence Handle10.1006/jmbi.1995.0556 Occurrence Handle7563093
F. Dyda A.B. Hickman T.M. Jenkins A. Engelman R. Craigie D.R. Davies (1994) Science (Washington, D.C.) 266 1981
Y. Goldgur F. Dyda A.B. Hickman T.M. Jenkins R. Craigie D.R. Davies (1998) Proc. Natl. Acad. Sci. USA. 95 9150 Occurrence Handle10.1073/pnas.95.16.9150 Occurrence Handle9689049
Y. Goldgur R. Craigie G.H. Cohen T. Fujiwara T. Yoshinaga T. Fujishita H. Sugimoto T. Endo H. Murai D.R. Davies (1999) Proc. Natl. Acad. Sci. USA. 96 13040 Occurrence Handle10.1073/pnas.96.23.13040 Occurrence Handle10557269
J. Lubkowski F. Yang J. Alexandratos A. Wlodawer H. Zhao T.R. Burke SuffixJr. N. Neamati Y. Pommier G. Merkel A.M. Skalka (1998) Proc. Natl. Acad. Sci. USA. 95 4831 Occurrence Handle10.1073/pnas.95.9.4831 Occurrence Handle9560188
J. Lubkowski Z. Dauter F. Yang J. Alexandratos G. Merkel A.M. Skalka A. Wlodawer (1999) Biochemistry 38 13512 Occurrence Handle10.1021/bi991362q Occurrence Handle10521258
S. Maignan J.P. Guilloteau Q. Zhou-Liu C. Clement-Mella V. Mikol (1998) J. Mol. Biol. 282 359 Occurrence Handle10.1006/jmbi.1998.2002 Occurrence Handle9735293
P.J. Lodi J.A. Ernst J. Kuszewski A.B. Hickman A. Engelman R. Craigie G.M. Clore A.M. Gronenborn (1995) Biochemistry 34 9826 Occurrence Handle10.1021/bi00031a002 Occurrence Handle7632683
A. Eijkelenboom R. Sprangers K. Hard R.A.P. Lutzke R.H.A. Plasterk R. Boelens R. Kaptein (1999) Proteins: Struct., Funct., Genet. 36 556
A. Eijkelenboom F.M.I. Vandenent A. Vos J.F. Doreleijers K. Hard T.D. Tullius R.H.A. Plasterk R. Kaptein R. Boelens (1997) Curr. Biol. 7 739 Occurrence Handle10.1016/S0960-9822(06)00332-0 Occurrence Handle9368756
M.L. Cai R.L. Zheng M. Caffrey R. Craigie G.M. Clore A.M. Gronenborn (1997) Nat. Struct. Biol. 4 839 Occurrence Handle10.1038/nsb0797-567
M.L. Cai Y. Huang M. Caffrey R.L. Zheng R. Craigie G.M. Clore A.M. Gronenborn (1998) Protein Sci. 7 2669 Occurrence Handle9865962
T.S. Heuer P.O. Brown (1997) Biochemistry 36 10655 Occurrence Handle10.1021/bi970782h Occurrence Handle9271496
D. Esposito R. Craigie (1998) EMBO J. 17 5832 Occurrence Handle10.1093/emboj/17.19.5832 Occurrence Handle9755183
C. Vink A.M. Oude Groeneger R.H. Plasterk (1993) Nucl. Acids Res. 21 1419 Occurrence Handle8464733
F.D. Bushman A. Engelman I. Palmer P. Wingfield R. Craigie (1993) Proc. Natl. Acad. Sci. USA. 90 3428 Occurrence Handle8386373
R. Zheng T.M. Jenkins R. Craigie (1996) Proc. Natl. Acad. Sci. USA. 93 13659 Occurrence Handle10.1073/pnas.93.24.13659 Occurrence Handle8942990
F.M. Ent Particlevan den A. Vos R.H. Plasterk (1999) J. Virol. 73 3176 Occurrence Handle10074170
V. Ellison J. Gerton K.A. Vincent P.O. Brown (1995) J. Biol. Chem. 270 3320 Occurrence Handle10.1074/jbc.270.7.3320 Occurrence Handle7852418
P.A. Rice T.A. Baker (2001) Nat. Struct. Biol. 8 302 Occurrence Handle10.1038/86166
A. Engelman R. Craigie (1992) J. Virol. 66 6361 Occurrence Handle1404595
A.D. Leavitt L. Shiue H.E. Varmus (1993) J. Biol. Chem. 268 2113 Occurrence Handle8420982
D.C. Gent ParticleVan A.A.M. Oude Groeneger R.H.A. Plasterk (1992) Proc. Natl. Acad. Sci. USA. 89 9598 Occurrence Handle1409671
P.M. Cannon W. Wilson E. Byles S.M. Kingsman A.J. Kingsman (1994) J. Virol. 68 4768 Occurrence Handle8035478
A. Engelman G. Englund J.M. Orenstein M.A. Martin R. Craigie (1995) J. Virol. 69 2729 Occurrence Handle7535863
A. Engelman A.B. Hickman R. Craigie (1994) J. Virol. 68 5911 Occurrence Handle8057470
R.A. Lutzke C. Vink R.H. Plasterk (1994) Nucl. Acids Res. 22 4125 Occurrence Handle7937137
S.R. Mumm D.P. Grandgenett (1991) J. Virol. 65 1160 Occurrence Handle1847445
A. Eijkelenboom R.A.P. Lutzke R. Boelens R.H.A. Plasterk R. Kaptein K. Hard (1995) Nat. Struct. Biol. 2 807 Occurrence Handle10.1038/nsb0995-807 Occurrence Handle7552753
K. Zhu C. Dobard S.A. Chow (2004) J. Virol. 78 5045 Occurrence Handle10.1128/JVI.78.10.5045-5055.2004 Occurrence Handle15113886
E.A. Hehl P. Joshi G.V. Kalpana V.R. Prasad (2004) J. Virol. 78 5056 Occurrence Handle10.1128/JVI.78.10.5056-5067.2004 Occurrence Handle15113887
J.P.G. Mack J. Theochem (1998) Mol. Struct. 423 41
D.R. Davies L.M. Braam W.S. Reznikoff I. Rayment (1999) J. Biol. Chem. 274 11904 Occurrence Handle10.1074/jbc.274.17.11904 Occurrence Handle10207011
D.R. Davies I.Y. Goryshin W.S. Reznikoff I. Rayment (2000) Science (Washington, D.C.) 289 77
L. Haren B. Ton-Hoang M. Chandler (1999) Annu. Rev. Microbiol. 53 245 Occurrence Handle10.1146/annurev.micro.53.1.245 Occurrence Handle10547692
W.S. Reznikoff (2003) Mol. Microbiol. 47 1199 Occurrence Handle10.1046/j.1365-2958.2003.03382.x Occurrence Handle12603728
P. Rice R. Craigie D.R. Davies (1996) Curr. Opin. Struct. Biol. 6 76 Occurrence Handle10.1016/S0959-440X(96)80098-4 Occurrence Handle8696976
T.L. Williams T.A. Baker (2000) Science (Washington, D.C.) 289 73
T.M. Jenkins D. Esposito A. Engelman R. Craigie (1997) EMBO J. 16 6849 Occurrence Handle10.1093/emboj/16.22.6849 Occurrence Handle9362498
P.J. Goodford (1985) J. Med. Chem. 28 849 Occurrence Handle10.1021/jm00145a002 Occurrence Handle3892003
L. Holm C. Sander (1999) Nucl. Acids Res. 27 244 Occurrence Handle10.1093/nar/27.1.244 Occurrence Handle9847191
C. Kuiken B. Foley B. Hahn P. Marx F. McCutchan J. Mellors S. Wolinsky B. Korber (Eds) (2001) HIV Sequence Compendium 2001: Theoretical Biology and Biophysics Group Los Alamos National Laboratory Los Alamos, NM
D. Pruss F.D. Bushman A.P. Wolffe (1994) Proc. Natl. Acad. Sci. USA. 91 5913 Occurrence Handle8016088
D. Pruss R. Reeves F.D. Bushman A.P. Wolffe (1994) J. Biol. Chem. 269 25031 Occurrence Handle7929189
P.M. Pryciak H.E. Varmus (1992) Cell 69 769 Occurrence Handle10.1016/0092-8674(92)90289-O Occurrence Handle1317268
Y.C. Bor M.D. Miller F.D. Bushman L.E. Orgel (1996) Virology 222 283 Occurrence Handle10.1006/viro.1996.0422 Occurrence Handle8806511
R.A. Katz P. DiCandeloro G. Kukolj A.M. Skalka (2001) J. Biol. Chem. 276 34213 Occurrence Handle10.1074/jbc.M104632200 Occurrence Handle11441016
T.M. Jenkins A. Engelman R. Ghirlando R. Craigie (1996) J. Biol. Chem. 271 7712 Occurrence Handle10.1074/jbc.271.13.7712 Occurrence Handle8631811
M.D. Andrake A.M. Skalka (1995) J. Biol. Chem. 270 29299 Occurrence Handle10.1074/jbc.270.49.29299 Occurrence Handle7493962
E. Deprez P. Tauc H. Leh J.F. Mouscadet C. Auclair J.C. Brochon (2000) Biochemistry 39 9275 Occurrence Handle10.1021/bi000397j Occurrence Handle10924120
H. Leh P. Brodin J. Bischerour E. Deprez P. Tauc J.C. Brochon E. LeCam D. Coulaud C. Auclair J.F. Mouscadet (2000) Biochemistry 39 9285 Occurrence Handle10.1021/bi000398b Occurrence Handle10924121
E. Asante-Appiah A.M. Skalka (1999) Adv. Virus Res. 52 351 Occurrence Handle10384242
E. Asante-Appiah A.M. Skalka (1997) J. Biol. Chem. 272 16196 Occurrence Handle10.1074/jbc.272.26.16196 Occurrence Handle9195919
C. Vink R.A. Lutzke R.H. Plasterk (1994) Nucl. Acids Res. 22 4103 Occurrence Handle7937134
van Gent, D.C., Vink, C., Groeneger, A.A. and Plasterk, R.H., EMBO J., 12 (1993) 3261.
Engelman, A., Bushman, F.D. and Craigie, R., EMBO J., 12 (1993) 3269.
K.K. Bao H. Wang J.K. Miller D.A. Erie A.M. Skalka I. Wong (2003) J. Biol. Chem. 278 1323 Occurrence Handle10.1074/jbc.C200550200 Occurrence Handle12446721
W. Yang T.A. Steitz (1995) Structure 3 131 Occurrence Handle10.1016/S0969-2126(01)00142-3 Occurrence Handle7735828
E. Khan J.P. Mack R.A. Katz J. Kulkosky A.M. Skalka (1991) Nucl. Acids Res. 19 851 Occurrence Handle1850126
K. Sayasith G. Sauve J. Yelle (2000) Mol. Cells 10 525 Occurrence Handle11101143
A.M. Dirac J. Kjems (2001) Eur. J. Biochem. 268 743 Occurrence Handle10.1046/j.1432-1327.2001.01932.x Occurrence Handle11168414
M.L. Connolly (1983) Science (Washington, D.C.) 221 709
A. Engelman Y. Liu H.M. Chen M. Farzan F. Dyda (1997) J. Virol. 71 3507 Occurrence Handle9094622
A.L. Harper L.M. Skinner M. Sudol M. Katzman (2001) J. Virol. 75 7756 Occurrence Handle10.1128/JVI.75.16.7756-7762.2001 Occurrence Handle11462051
R.S. Appa C.G. Shin P. Lee S.A. Chow (2001) J. Biol. Chem. 276 45848 Occurrence Handle10.1074/jbc.M107365200 Occurrence Handle11585830
K.A. Vincent V. Ellison S.A. Chow P.O. Brown (1993) J. Virol. 67 425 Occurrence Handle8416376
S.A. Chow P.O. Brown (1994) J. Virol. 68 7869 Occurrence Handle7966577
A. Engelman (1999) Adv. Virus Res. 52 411 Occurrence Handle10384245
M. Wiskerchen M.A. Muesing (1995) J. Virol. 69 376 Occurrence Handle7983732
J.L. Gerton S. Ohgi M. Olsen J. Derisi P.O. Brown (1998) J. Virol. 72 5046 Occurrence Handle9573274
J. Greenwald V. Le S.L. Butler F.D. Bushman S. Choe (1999) Biochemistry 38 8892 Occurrence Handle10.1021/bi9907173 Occurrence Handle10413462
M.L. Barreca K.W. Lee A. Chimirri J.M. Briggs (2003) Biophys. J. 84 1450 Occurrence Handle12609852
R.D. Lins J.M. Briggs T.P. Straatsma H.A. Carlson J. Greenwald S. Choe J.A. McCammon (1999) Biophys. J. 76 2999 Occurrence Handle10354426
W. Weber H. Demirdjian R.D. Lins J.M. Briggs R. Ferreira J.A. McCammon (1998) J. Biomol. Struct. Dyn. 16 733 Occurrence Handle10052629
H. Ni C.A. Sotriffer J.A. McCammon (2001) J. Med. Chem. 44 3043 Occurrence Handle10.1021/jm010205y Occurrence Handle11543671
Y. Pommier A.A. Pilon K. Bajaj A. Mazumder N. Neamati (1997) Antiviral Chem. Chemother. 8 463
F.M. Ent Particlevan den A. Vos R.H. Plasterk (1998) J. Virol. 72 3916 Occurrence Handle9557677
K.M. McGrath N.G. Hoffman W. Resch J.A. Nelson R. Swanstrom (2001) Virus Res. 76 137 Occurrence Handle10.1016/S0168-1702(01)00271-4 Occurrence Handle11410314
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wielens, J., Crosby, I.T. & Chalmers, D.K. A Three-dimensional Model of the Human Immunodeficiency Virus Type 1 Integration Complex. J Comput Aided Mol Des 19, 301–317 (2005). https://doi.org/10.1007/s10822-005-5256-2
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/s10822-005-5256-2