Abstract
Site-specific substitutions of as few as four amino acids (M46I/L63P/V82T/I84V) of the human immunodeficiency virus type 1 (HIV-1) protease engenders cross-resistance to a panel of protease inhibitors that are either in clinical trials or have recently been approved for HIV therapy (Condra, J. H., Schleif, W. A., Blahy, O. M. , Gadryelski, L. J., Graham, D. J., Quintero, J. C., Rhodes, A., Robbins, H. L., Roth, E., Shivaprakash, M., Titus, D., Yang, T., Teppler, H., Squires, K. E., Deutsch, P. J., and Emini, E. A. (1995) Nature 374, 569-571). These four substitutions are among the prominent mutations found in primary HIV isolates obtained from patients undergoing therapy with several protease inhibitors. Two of these mutations (V82T/I84V) are located in, while the other two (M46I/L63P) are away from, the binding cleft of the enzyme. The functional role of these mutations has now been delineated in terms of their influence on the binding affinity and catalytic efficiency of the protease. We have found that the double substitutions of M46I and L63P do not affect binding but instead endow the enzyme with a catalytic efficiency significantly exceeding (110-360%) that of the wild-type enzyme. In contrast, the double substitutions of...Continue Reading
References
May 26, 1992·Biochemistry·J TözsérS Oroszlan
Jun 9, 1992·Biochemistry·J T GriffithsJ Kay
Dec 1, 1991·Antiviral Research·J C CraigJ S Mills
Feb 25, 1991·FEBS Letters·J TözsérS Oroszlan
Apr 9, 1991·FEBS Letters·J TözsérS Oroszlan
Jan 24, 1985·Nature·L RatnerK Baumeister
Mar 8, 1988·Biochemistry·A R FershtG Winter
Aug 1, 1995·Antimicrobial Agents and Chemotherapy·M TisdaleE D Blair
Jan 12, 1995·Nature·X WeiB H Hahn
May 1, 1995·Journal of Virology·J R RoséC S Craik
Jun 1, 1995·AIDS Research and Human Retroviruses·J EberleH Nitschko
Jul 25, 1995·Biochemistry·S V GulnikJ W Erickson
Sep 1, 1995·Journal of Virology·J A PartaledisA B Cullinan
Jul 1, 1995·Nature Structural Biology·J W Erickson
Sep 15, 1995·The Journal of Biological Chemistry·Z ChenL C Kuo
Apr 6, 1995·Nature·J H CondraM Shivaprakash
Mar 28, 1995·Proceedings of the National Academy of Sciences of the United States of America·D J KempfX P Kong
Jan 1, 1995·AIDS Research and Human Retroviruses·D L WinslowM J Otto
Mar 1, 1995·Nature Structural Biology·E T BaldwinJ W Erickson
Feb 1, 1995·Journal of Virology·M MarkowitzD D Ho
Jan 12, 1995·Nature·D D HoM Markowitz
Jan 27, 1995·Science·J M Coffin
Jan 31, 1995·Biochemistry·Y LinB M Dunn
Jan 10, 1995·Virology·H JacobsenJ Mous
Jan 1, 1994·Methods in Enzymology·B M DunnJ Kay
Jan 1, 1994·Methods in Enzymology·A G Tomasselli, R L Heinrikson
Oct 14, 1994·Journal of Medicinal Chemistry·B D DorseyJ C Quintero
Dec 1, 1994·Journal of Virology·S C PettitR Swanstrom
Dec 1, 1994·Journal of Virology·B TaddeoC M Farnet
Mar 1, 1994·Journal of Virology·D D HoM K Singh
Mar 1, 1994·Biochemistry·V V SardanaR L LaFemina
Jun 7, 1994·Proceedings of the National Academy of Sciences of the United States of America·A H KaplanR Swanstrom
Jan 1, 1994·Journal of Virology·M A el-FarrashS Harada
Jan 11, 1994·Biochemistry·P L DarkeL C Kuo
Aug 15, 1993·Proceedings of the National Academy of Sciences of the United States of America·M J OttoY S Cheng
Jul 1, 1993·The Journal of Pediatrics·R N HussonH Mitsuya
Dec 6, 1995·Biochimica Et Biophysica Acta·K Yamaguchi, R A Byrn
Mar 1, 1996·The Journal of Biological Chemistry·T W RidkyR W Harrison
Jul 26, 1996·The Journal of Biological Chemistry·S PazhanisamyD J Livingston
Sep 1, 1964·Biochemistry·R B MERRIFIELD
Aug 8, 1986·Science·D A EstellP G Ng
Citations
Dec 13, 2000·Reviews in Medical Virology·A Telenti, G Paolo Rizzardi
Apr 27, 2005·Chirality·Hideki IshiiNina Berova
Sep 6, 2001·Journal of Medical Virology·H L DevereuxC Loveday
Jun 8, 2002·Journal of Molecular Biology·Stefano PianaMichele Parrinello
May 9, 2000·Pharmacology & Therapeutics·R Swanstrom, J Erona
Oct 1, 1998·Antiviral Research·A MollaD J Kempf
Jun 19, 2001·Virus Research·K M McGrathR Swanstrom
Jan 6, 2001·Infectious Disease Clinics of North America·N A Kartsonis, R T D'Aquila
Aug 6, 2002·Bioorganic & Medicinal Chemistry Letters·Joseph L DuffyJames R Tata
Jul 11, 2003·Bioorganic & Medicinal Chemistry Letters·Fengqi ZhangJames R Tata
Sep 13, 2001·Journal of Molecular Graphics & Modelling·Y Z ChenZ W Cao
Aug 4, 2009·Journal of the American Chemical Society·Fabio PietrucciAlessandro Laio
Jan 5, 1999·Haemophilia : the Official Journal of the World Federation of Hemophilia·J H Condra
Aug 16, 2002·European Journal of Biochemistry·Anita FehérJózsef Tözsér
Feb 16, 2012·The Journal of Biological Chemistry·Sook-Kyung LeeRonald Swanstrom
Oct 9, 2012·The Journal of Biological Chemistry·Sook-Kyung LeeRonald Swanstrom
Feb 7, 2001·The Journal of Experimental Medicine·A D KelleherR E Phillips
May 26, 2001·AIDS Research and Human Retroviruses·K KanbaraH Nakashima
Aug 1, 1998·AIDS Research and Human Retroviruses·S C PettitR Swanstrom
Nov 5, 1999·AIDS·E RaceF Clavel
Jan 12, 2000·AIDS·H L DevereuxC Loveday
Sep 19, 2002·Protein Science : a Publication of the Protein Society·Stefano PianaUrsula Rothlisberger
Jan 16, 2002·Protein Science : a Publication of the Protein Society·Nancy M KingCelia A Schiffer
Apr 21, 1999·Protein Science : a Publication of the Protein Society·J TrylskaM K Gilson
Dec 14, 1999·Protein Science : a Publication of the Protein Society·D XieA S Gulnik
Nov 16, 2011·Antimicrobial Agents and Chemotherapy·Gavin J HendersonRonald Swanstrom
Jan 25, 2003·Antimicrobial Agents and Chemotherapy·Terri WatkinsRonald Swanstrom
Aug 30, 2005·Antimicrobial Agents and Chemotherapy·S WeinheimerR Colonno
Oct 16, 2007·Clinical Microbiology Reviews·Carrie Dykes, Lisa M Demeter
Jul 20, 2001·Journal of Virology·D J KempfR A Rode
Sep 5, 2001·Journal of Virology·B BühlerB E Torbett
Oct 17, 2001·Journal of Virology·E Y KimT C Merigan
Mar 10, 2001·Journal of Virology·G BleiberA Telenti
Aug 7, 2002·Journal of Virology·Wolfgang ReschRonald Swanstrom
Dec 28, 2002·Journal of Virology·Moses Prabu-JeyabalanCelia A Schiffer
Mar 29, 2003·Journal of Virology·Thomas D WuRobert W Shafer
Dec 13, 2003·Journal of Virology·Alexey A NabatovWilliam A Paxton
Oct 14, 2004·Journal of Virology·Nancy M KingCelia A Schiffer
Oct 14, 2004·Journal of Virology·Sadahiro TamiyaHiroaki Mistuya
Jul 30, 2005·Journal of Virology·Wolfgang ReschRonald Swanstrom
Oct 6, 1998·Annual Review of Biochemistry·A D Frankel, J A Young
Mar 4, 2009·Annual Review of Biochemistry·Peter M Colman
Jul 1, 1998·Annual Review of Biophysics and Biomolecular Structure·A Wlodawer, J Vondrasek
Nov 3, 1998·Artificial Life·C D RosinD S Goodsell
Nov 28, 2007·PLoS Computational Biology·Art F Y PoonSimon D W Frost
Apr 18, 1998·Proceedings of the National Academy of Sciences of the United States of America·H J Sices, T M Kristie
May 11, 2000·Proceedings of the National Academy of Sciences of the United States of America·J G BishopT Mitchell-Olds
Feb 17, 1999·Proceedings of the National Academy of Sciences of the United States of America·C D RosinD S Goodsell
Feb 20, 2016·Biochemistry·Rajeswari Appadurai, Sanjib Senapati
Jul 19, 2011·Journal of Molecular Biology·Max W Chang, Bruce E Torbett