Three-dimensional structure of an fab-peptide complex: structural basis of HIV-1 protease inhibition by a monoclonal antibody
| Autor: | V. Chitarra, J. Lescar, Magda Horejsi, Milan Fábry, Juraj Sedlacek, M.-M. Riottot, Renata Stouracova, Jiri Brynda, Graham A. Bentley |
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| Rok vydání: | 1997 |
| Předmět: |
Models
Molecular Structural similarity Stereochemistry medicine.medical_treatment Proteolysis Molecular Sequence Data Peptide Cross Reactions Crystallography X-Ray Antiparallel (biochemistry) Immunoglobulin Fab Fragments HIV Protease HIV-1 protease Structural Biology medicine Computer Simulation Amino Acid Sequence Cloning Molecular Tyrosine Molecular Biology chemistry.chemical_classification Binding Sites Hybridomas Protease Base Sequence medicine.diagnostic_test biology Antibodies Monoclonal HIV Protease Inhibitors Sequence Analysis DNA Enzyme chemistry biology.protein |
| Zdroj: | Journal of Molecular Biology. 267:1207-1222 |
| ISSN: | 0022-2836 |
| DOI: | 10.1006/jmbi.1997.0950 |
| Popis: | F11.2.32, a monoclonal antibody raised against HIV-1 protease ( K d =5 nM), which inhibits proteolytic activity of the enzyme ( K inh =35(±3) nM), has been studied by crystallographic methods. The three-dimensional structure of the complex between the Fab fragment and a synthetic peptide, spanning residues 36 to 46 of the protease, has been determined at 2.2 A resolution, and that of the Fab in the free state has been determined at 2.6 A resolution. The refined model of the complex reveals ten well-ordered residues of the peptide (P36 to P45) bound in a hydrophobic cavity at the centre of the antigen-binding site. The peptide adopts a β hairpin-like structure in which residues P38 to P42 form a type II β-turn conformation. An intermolecular antiparallel β-sheet is formed between the peptide and the CDR3-H loop of the antibody; additional polar interactions occur between main-chain atoms of the peptide and hydroxyl groups from tyrosine residues protruding from CDR1-L and CDR3-H. Three water molecules, located at the antigen-antibody interface, mediate polar interactions between the peptide and the most buried hypervariable loops, CDR3-L and CDR1-H. A comparison between the free and complexed Fab fragments shows that significant conformational changes occur in the long hypervariable regions, CDR1-L and CDR3-H, upon binding the peptide. The conformation of the bound peptide, which shows no overall structural similarity to the corresponding segment in HIV-1 protease, suggests that F11.2.32 might inhibit proteolysis by distorting the native structure of the enzyme. |
| Databáze: | OpenAIRE |
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