1fb7: Difference between revisions
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'''CRYSTAL STRUCTURE OF AN IN VIVO HIV-1 PROTEASE MUTANT IN COMPLEX WITH SAQUINAVIR: INSIGHTS INTO THE MECHANISMS OF DRUG RESISTANCE''' | {{Structure | ||
|PDB= 1fb7 |SIZE=350|CAPTION= <scene name='initialview01'>1fb7</scene>, resolution 2.6Å | |||
|SITE= | |||
|LIGAND= <scene name='pdbligand=ROC:CIS-N-TERT-BUTYL-DECAHYDRO-2-[2(R)-HYDROXY-4-PHENYL-3(S)-[[N-2-QUINOLYLCARBONYL-L-ASPARAGINYL]AMINO]BUTYL]-(4AS)-ISOQUINOLINE-3(S)-CARBOXAMIDE'>ROC</scene> | |||
|ACTIVITY= | |||
|GENE= | |||
}} | |||
'''CRYSTAL STRUCTURE OF AN IN VIVO HIV-1 PROTEASE MUTANT IN COMPLEX WITH SAQUINAVIR: INSIGHTS INTO THE MECHANISMS OF DRUG RESISTANCE''' | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
1FB7 is a [ | 1FB7 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1FB7 OCA]. | ||
==Reference== | ==Reference== | ||
Crystal structure of an in vivo HIV-1 protease mutant in complex with saquinavir: insights into the mechanisms of drug resistance., Hong L, Zhang XC, Hartsuck JA, Tang J, Protein Sci. 2000 Oct;9(10):1898-904. PMID:[http:// | Crystal structure of an in vivo HIV-1 protease mutant in complex with saquinavir: insights into the mechanisms of drug resistance., Hong L, Zhang XC, Hartsuck JA, Tang J, Protein Sci. 2000 Oct;9(10):1898-904. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/11106162 11106162] | ||
[[Category: Human immunodeficiency virus 1]] | [[Category: Human immunodeficiency virus 1]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
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[[Category: x-ray]] | [[Category: x-ray]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 11:06:55 2008'' | ||
Revision as of 12:06, 20 March 2008
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CRYSTAL STRUCTURE OF AN IN VIVO HIV-1 PROTEASE MUTANT IN COMPLEX WITH SAQUINAVIR: INSIGHTS INTO THE MECHANISMS OF DRUG RESISTANCE
OverviewOverview
Saquinavir is a widely used HIV-1 protease inhibitor drug for AIDS therapy. Its effectiveness, however, has been hindered by the emergence of resistant mutations, a common problem for inhibitor drugs that target HIV-1 viral enzymes. Three HIV-1 protease mutant species, G48V, L90M, and G48V/L90M double mutant, are associated in vivo with saquinavir resistance by the enzyme (Jacobsen et al., 1996). Kinetic studies on these mutants demonstrate a 13.5-, 3-, and 419-fold increase in Ki values, respectively, compared to the wild-type enzyme (Ermolieff J, Lin X, Tang J, 1997, Biochemistry 36:12364-12370). To gain an understanding of how these mutations modulate inhibitor binding, we have solved the HIV-1 protease crystal structure of the G48V/L90M double mutant in complex with saquinavir at 2.6 A resolution. This mutant complex is compared with that of the wild-type enzyme bound to the same inhibitor (Krohn A, Redshaw S, Richie JC, Graves BJ, Hatada MH, 1991, J Med Chem 34:3340-3342). Our analysis shows that to accommodate a valine side chain at position 48, the inhibitor moves away from the protease, resulting in the formation of larger gaps between the inhibitor P3 subsite and the flap region of the enzyme. Other subsites also demonstrate reduced inhibitor interaction due to an overall change of inhibitor conformation. The new methionine side chain at position 90 has van der Waals interactions with main-chain atoms of the active site residues resulting in a decrease in the volume and the structural flexibility of S1/S1' substrate binding pockets. Indirect interactions between the mutant methionine side chain and the substrate scissile bond or the isostere part of the inhibitor may differ from those of the wild-type enzyme and therefore may facilitate catalysis by the resistant mutant.
About this StructureAbout this Structure
1FB7 is a Single protein structure of sequence from Human immunodeficiency virus 1. Full crystallographic information is available from OCA.
ReferenceReference
Crystal structure of an in vivo HIV-1 protease mutant in complex with saquinavir: insights into the mechanisms of drug resistance., Hong L, Zhang XC, Hartsuck JA, Tang J, Protein Sci. 2000 Oct;9(10):1898-904. PMID:11106162
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