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FEBS Lett 1997 Dec 22;420(1):11-6

Structure of a G48H mutant of HIV-1 protease explains how glycine-48 replacements produce mutants resistant to inhibitor drugs.

Hong L, Zhang XJ, Foundling S, Hartsuck JA, Tang J

Protein Studies Program, Oklahoma Medical Research Foundation, Oklahoma City 73104, USA.

The crystal structure of human immunodeficiency virus type 1 (HIV-1) protease mutant G48H with peptidic inhibitor U-89360E is described. Comparison with wild-type protease-inhibitor complex shows that mutation of flap residue 48 to histidine allows stabilizing van der Waals contacts between the side chains of His48 and Phe53 as well as between His48 and the P2' and P3' inhibitor subsites. The flap region is less mobile than in the wild-type enzyme. A model of saquinavir-resistant mutant protease G48V in complex with saquinavir predicts interactions similar to those found in the G48H crystal. Energetic calculations confirm the similarity of the His48 and Val48 interactions.

MeSH Terms:

• Drug Resistance, Microbial
• Glycine/chemistry*
• Human
• HIV Protease/genetics
• HIV Protease/chemistry*
• HIV Protease Inhibitors/pharmacology
• HIV Protease Inhibitors/chemistry*
• HIV-1/enzymology*
• HIV-1/drug effects
• Models, Molecular
• Mutation*
• Oligopeptides/pharmacology
• Oligopeptides/chemistry
• Saquinavir/chemistry
• Support, U.S. Gov't, P.H.S.

Substances:

• Glycine
• U 89360E
• Saquinavir
• Oligopeptides
• HIV Protease Inhibitors
• HIV Protease

Grant support:

• AI-38189/AI/NIAID

Other Formats:
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Biochemistry 1996 Aug 20;35(33):10627-33

Crystal structures of complexes of a peptidic inhibitor with wild-type and two mutant HIV-1 proteases.

Hong L, Treharne A, Hartsuck JA, Foundling S, Tang J

Protein Studies Program, Oklahoma Medical Research Foundation, University of Oklahoma Health Sciences Center, Oklahoma City 73104, USA.

Crystal structures of the protease of human immunodeficiency virus type 1 (HIV-1) and two mutant proteases, V82D and V82N, have been determined. In all three cases the enzyme forms a complex with the peptidic inhibitor U-89360E. All structures have been determined to 2.3 A resolution and have satisfactory agreement factors: 0.173 for wild type, 0.175 for V82D, and 0.182 for V82N. Comparison of the three crystal structures provides explanations which are consistent with the known kinetic properties of these mutant enzymes with the U-89360E inhibitor [Lin, Y., Lin, X., Hong, L., Foundling, S., Heinrikson, R. L., Thaisrivongs, S., Leelamanit, W., Raterman, D., Shah, M., Dunn, B.M., & Tang, J. (1995) Biochemistry 34, 1143-1152]. Unfavorable van der Waals interactions between the inhibitor and the mutated side chains at position 82 are consistent with diminished affinity for the inhibitor by the mutant enzymes. If a mutation is potentially resistant to an inhibitor, the mutant enzyme should not only have an increased Ki for the inhibitor but should also preserve considerable catalytic capability. The V82D mutant possesses these qualities. In the V82D crystal structure, a water molecule, which connects the protease flap to the inhibitor, is missing or of low occupancy. Absence of this bridge may be important in determining catalytic capability. Moreover, mutation at position 82 induces change in two polypeptide backbone regions, 35-41 and 67-68, which may be related to protease flap mobility.

MeSH Terms:

• Crystallography, X-Ray
• HIV Protease/genetics
• HIV Protease/chemistry*
• HIV Protease Inhibitors/chemistry*
• HIV-1/enzymology*
• Models, Molecular
• Mutagenesis
• Oligopeptides/chemistry*
• Support, U.S. Gov't, P.H.S.

Substances:

• U 89360E
• Oligopeptides
• HIV Protease Inhibitors
• HIV Protease

Secondary source id:

• PDB/1GNN
• PDB/1GNM
• PDB/1GNO

Grant support:

• AI-38189/AI/NIAID

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