Structural Maturation of HIV-1 Reverse Transcriptase-A Metamorphic Solution to Genomic Instability.
Human immunodeficiency virus 1 (HIV-1) reverse transcriptase (RT)-a critical enzyme of the viral life cycle-undergoes a complex maturation process, required so that a pair of p66 precursor proteins can develop conformationally along different pathways, one evolving to form active polymerase and ribonuclease H (RH) domains, while the second forms a non-functional polymerase and a proteolyzed RH domain. These parallel maturation pathways rely on the structural ambiguity of a metamorphic polymerase domain, for which the sequence-structure relationship is not unique. Recent nuclear magnetic resonance (NMR) studies utilizing selective labeling techniques, and structural characterization of the p66 monomer precursor have provided important insights into the details of this maturation pathway, revealing many aspects of the three major steps involved: (1) domain rearrangement; (2) dimerization; and (3) subunit-selective RH domain proteolysis. This review summarizes the major structural changes that occur during the maturation process. We also highlight how mutations, often viewed within the context of the mature RT heterodimer, can exert a major influence on maturation and dimerization. It is further suggested that several steps in the RT maturation pathway may provide attractive targets for drug development.
Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA. london@niehs.nih.gov.
Robert E
RE
London
HIV-1 reverse transcriptase; RNase H domain; metamorphic protein; reverse transcriptase maturation pathway; structural heterodimer; subunit-specific RNase H domain unfolding
J Mol Biol. 1994 Oct 28;243(3):369-87
7525966
J Biol Chem. 1991 Apr 5;266(10):6230-9
1706712
Curr HIV Res. 2008 Mar;6(2):130-7
18336260
Antimicrob Agents Chemother. 2015 Jan;59(1):590-8
25385110
Antimicrob Agents Chemother. 1995 Oct;39(10):2253-7
8619578
Proteins. 2014 Oct;82(10):2343-52
24771554
Nucleic Acids Res. 2012 Nov 1;40(20):10543-53
22941642
J Virol. 2005 Aug;79(16):10718-29
16051864
EMBO Rep. 2001 Jul;2(7):580-5
11463741
J Virol. 2001 Jun;75(11):4999-5008
11333879
Biochemistry. 1996 Jul 2;35(26):8553-62
8679616
Nat Struct Biol. 1999 Sep;6(9):868-75
10467100
Science. 1998 Nov 27;282(5394):1669-75
9831551
BMC Biochem. 2002 Jun 18;3:18
12086585
Eur J Biochem. 2001 Mar;268(5):1163-72
11231267
Nucleic Acids Res. 2003 Jul 1;31(13):3316-9
12824316
Biochemistry. 1992 Sep 29;31(38):9150-7
1382587
Science. 1988 Nov 25;242(4882):1171-3
2460925
Nucleic Acids Res. 2014 Apr;42(8):5361-77
24574528
Nucleic Acids Res. 1995 Jul 11;23(13):2434-41
7543198
Antimicrob Agents Chemother. 1998 Jun;42(6):1340-5
9624472
Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):7242-6
7518928
FEBS Lett. 1994 Apr 25;343(2):125-30
7513287
Virus Res. 2008 Jun;134(1-2):39-63
18279991
ACS Chem Biol. 2008 Oct 17;3(10):635-44
18831589
J Mol Recognit. 1994 Jun;7(2):157-61
7530020
Annu Rev Biochem. 1994;63:133-73
7526778
PLoS Pathog. 2006 Nov;2(11):e119
17096588
J Virol. 2013 Mar;87(6):3348-60
23302874
J Med Chem. 2004 May 6;47(10):2550-60
15115397
Cell Host Microbe. 2008 Jun 12;3(6):388-98
18541215
FEBS Lett. 2005 Apr 25;579(11):2294-300
15848161
AIDS. 2011 May 15;25(8):1123-6
21505320
Biochemistry. 1993 Dec 7;32(48):13012-8
7694651
J Virol. 2007 Dec;81(23):12899-910
17881447
J Virol. 2004 Feb;78(4):2082-7
14747573
J Biol Chem. 2012 Feb 3;287(6):4066-75
22105069
Structure. 2003 Mar;11(3):243-51
12623012
EMBO J. 2001 Mar 15;20(6):1449-61
11250910
J Med Chem. 2009 Oct 22;52(20):6413-20
19827836
Antiviral Res. 2006 Jun;70(2):66-74
16472877
J Clin Virol. 2005 Dec;34(4):233-44
16198625
Proteins. 2005 Jul 1;60(1):5-13
15852304
J Biol Chem. 1992 Jul 15;267(20):14227-32
1378437
Mol Pharmacol. 2002 Aug;62(2):398-405
12130693
J Med Chem. 2013 Jul 11;56(13):5436-45
23631411
Eur J Biochem. 2002 Nov;269(21):5103-11
12392542
Curr Opin Struct Biol. 2010 Aug;20(4):482-8
20591649
Antimicrob Agents Chemother. 2010 Sep;54(9):3913-21
20547794
Antiviral Res. 2007 Nov;76(2):99-103
17640745
J Biol Chem. 2009 Jan 2;284(1):254-64
18952602
Trends Microbiol. 2003 Dec;11(12):543-6
14659685
FEBS Lett. 1993 Jun 14;324(2):153-8
7685295
Structure. 1999 Feb 15;7(2):R31-5
10368292
Biophys J. 1979 Jun;26(3):367-83
262423
PLoS Comput Biol. 2013;9(6):e1003103
23754941
Biochem J. 2007 May 15;404(1):151-7
17286555
Retrovirology. 2007 Oct 24;4:77
17956635
Chem Biol Drug Des. 2012 Nov;80(5):706-16
22846652
J Biol Chem. 1991 Dec 25;266(36):24359-66
1761538
J Mol Biol. 2007 Jan 5;365(1):77-89
17056061
J Med Chem. 2011 Apr 28;54(8):2727-37
21446702
Elife. 2015 Jun 03;4:null
26037594
J Virol. 2004 Jul;78(13):7089-96
15194785
Protein Sci. 1993 Dec;2(12):2167-76
7507754
Curr Pharm Des. 2006;12(15):1895-907
16724955
J Virol. 2005 Aug;79(16):10247-57
16051818
Structure. 2009 Dec 9;17(12):1625-35
20004166
Proteins. 2015 Aug;83(8):1526-38
26061827
Genome Res. 2007 Oct;17(10):1496-504
17785537
Biochemistry. 2004 Jul 27;43(29):9332-42
15260476
J Biol Chem. 1999 Apr 16;274(16):11283-8
10196217
Curr Opin Struct Biol. 2002 Feb;12(1):48-53
11839489
Virus Res. 2008 Jun;134(1-2):171-85
18308412
J Mol Biol. 2003 Feb 14;326(2):381-96
12559908
Curr Pharm Des. 2009;15(21):2508-19
19601847
Curr Top Med Chem. 2016;16(12 ):1343-9
26459806
FEBS Lett. 2005 Jan 17;579(2):379-84
15642347
J Mol Biol. 2010 Apr 9;397(4):967-78
20156454
J Mol Biol. 1998 Dec 11;284(4):1095-111
9837729
J Mol Biol. 2009 Jan 23;385(3):693-713
19022262
Biochem Biophys Res Commun. 1990 Mar 16;167(2):673-9
1690991
Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6334-9
10841542
Science. 2008 Jun 27;320(5884):1725-6
18583598
J Med Chem. 2006 Aug 10;49(16):4834-41
16884295
Biochemistry. 2009 Sep 29;48(38):9084-93
19715314
Retrovirology. 2010 Feb 01;7:6
20122159
Virology. 2006 May 10;348(2):462-74
16504235
Adv Exp Med Biol. 2012;747:137-52
22949116
J Biol Chem. 1994 May 6;269(18):13080-3
7513698
Retrovirology. 2005 Nov 01;2:66
16262906
Mol Cell Biochem. 2001 Sep;225(1-):135-44
11716355
FEBS Lett. 2010 Jan 21;584(2):359-65
19914238
Antimicrob Agents Chemother. 2012 Jun;56(6):3324-35
22391531
Int J Biochem Cell Biol. 2004 Sep;36(9):1836-47
15183348
J Mol Biol. 2008 May 30;379(2):317-30
18448122
Biochemistry. 2006 Mar 7;45(9):2779-89
16503633
Nature. 1988 Jan 21;331(6153):280-3
2447506
Biophys J. 2013 Jun 18;104(12):2695-705
23790378
Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14410-5
12386343
J Mol Model. 2008 Aug;14(8):769-75
18504624
Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7188-93
11416202
Annu Rev Biochem. 1978;47:251-76
354496
PLoS One. 2013 Aug 09;8(8):e71002
23951066
Nat Rev Drug Discov. 2003 Oct;2(10):812-22
14526384
J Biol Chem. 1990 Jun 5;265(16):8986-8
1693146
J Biol Chem. 1991 Aug 5;266(22):14697-702
1713588
PLoS One. 2008 Mar 12;3(3):e1781
18335052
Protein Sci. 1998 Oct;7(10):2164-74
9792104
AIDS. 2014 Nov 13;28(17):F1-8
25259833
Virus Res. 2008 Jun;134(1-2):124-46
18272247
Arch Virol. 1991;118(3-4):179-88
1712581
Nucleic Acids Res. 2013 Feb 1;41(3):1901-13
23248007
Nature. 1993 Apr 22;362(6422):709-15
8469282
J Virol. 2005 Sep;79(18):11952-61
16140771
Biochemistry. 2010 Apr 6;49(13):2821-33
20180596
Nat Struct Biol. 1995 Apr;2(4):303-8
7540935
J Mol Biol. 2007 Feb 2;365(5):1368-78
17141805
J Biol Chem. 1997 Jul 11;272(28):17581-7
9211905
Virology. 2001 Nov 25;290(2):300-8
11883194
Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):3374-9
25713345
J Mol Biol. 2004 Jul 9;340(3):615-25
15210358
Biochemistry. 2000 Feb 15;39(6):1427-33
10684624
J Virol. 1996 Feb;70(2):809-19
8551619
Science. 1989 Aug 11;245(4918):616-21
2548279
Structure. 2000 Oct 15;8(10):1089-94
11080630
PLoS Pathog. 2014 Feb 27;10(2):e1003982
24586176
Nat Struct Mol Biol. 2012 Jan 22;19(2):253-9
22266819
J Mol Biol. 2000 Aug 25;301(4):1029-39
10966802
Nucleic Acids Res. 2016 Feb 29;44(4):1776-88
26773054
Structure. 1996 Jul 15;4(7):853-60
8805568
Virus Res. 2005 Feb;107(2):215-28
15649567
J Virol Methods. 2008 Oct;153(1):7-15
18640157
Biochemistry. 1991 Jul 2;30(26):6351-6
1711368
J Virol. 2007 Jul;81(13):6837-45
17428874
Science. 1991 Apr 5;252(5002):88-95
1707186
J Mol Biol. 1995 Feb 3;245(5):508-21
7531247
Structure. 1994 Oct 15;2(10):953-61
7532533
Science. 1994 Jun 24;264(5167):1930-5
7516581
Biochemistry. 2003 Jan 28;42(3):639-50
12534276
Science. 1992 Jun 26;256(5065):1783-90
1377403
J Mol Biol. 2005 Jun 17;349(4):673-84
15893326
Nature. 2010 Mar 11;464(7286):232-6
20118915