Three-dimensional structure of an fab-peptide complex: structural basis of HIV-1 protease inhibition by a monoclonal antibody

Lescar, Julien; Stouracova, Renata; Riottot, Marie‐Madeleine; Chitarra, V.; Brynda, J.; Fábry, Milan; Hořejší, M.; Sedláček, Juraj; Bentley, G.A.

doi:10.1006/jmbi.1997.0950

Cited by 48 publications

(31 citation statements)

References 68 publications

(65 reference statements)

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“…The structure of the Fab fragment of F11.2.32 has been determined in the non-complexed state as well as a complex with HIV-1 protease peptides derived from the segments 36-46 [P36-P46; Lescar et al, 1996Lescar et al, , 1997; see plate 2(a) and (b)]. The set of canonical structures of the CDR regions (Al-Lazikani et al, 1997) defining the antigen-binding site is: CDR-L1, canonical structure no.…”

Section: Monoclonal Antibody F11232mentioning

confidence: 99%

“…The anti-protease mAbs were produced in BALB/c mice by the hybridoma technique (Köhler and Milstein, 1975) using recombinant HIV-1 protease as immunogen (Lescar et al, 1997(Lescar et al, , 1999Rezacova et al, 2001). Inhibition constants of the antibodies for proteolysis were determined by measuring the cleavage rate of the substrate KARVNleEF-(NO 2 )EANle using reverse-phase HPLC.…”

Section: Anti-hiv-1 Protease Monoclonal Antibodiesmentioning

confidence: 99%

“…Since the active site is inaccessible to antibodies, these protease-inhibiting mAbs should be directed to other regions of the enzyme. In this paper we describe two anti-HIV-1 protease mAbs, F11.2.32 (Lescar et al, 1996(Lescar et al, , 1997 and 1696 (Lescar, et al, 1999;Rezacova et al, 2001), which inhibit activity of the viral enzyme. Although we have not yet been able to crystallize these antibodies as complexes with the HIV protease itself, we have demonstrated their presence in solution.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of HIV protease by monoclonal antibodies

Řezáčová

Brynda

Fábry

et al. 2002

J of Molecular Recognition

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The protease of HIV plays a critical role in the maturation of the infectious particles of the virus. The enzyme has therefore been extensively studied with the objective of developing therapeutics that inhibit viral proliferation. We have produced monoclonal antibodies specific for the HIV-1 protease, and selected those that inhibit enzyme function for use as probes to study the enzyme's activity and as an eventual aid for the development of potential inhibitors targeted to regions other than the active site. We have characterized two such mAbs, F11.2.32 and 1696, which have inhibition constants in the low nanomolar range and which recognize epitopes from different regions of the protease. The crystal structures of the two antibodies, both in the free state as well as complexes with peptide fragments corresponding to their respective epitopes, have been solved. The structural analyses, taken together with other functional data on the antibodies, suggest mechanisms of protease inhibition by these antibodies.

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Section: Monoclonal Antibody F11232mentioning

confidence: 99%

Section: Anti-hiv-1 Protease Monoclonal Antibodiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibition of HIV protease by monoclonal antibodies

Řezáčová

Brynda

Fábry

et al. 2002

J of Molecular Recognition

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“…Two fragments (fl1.2.32 and Opg2) have been solved in both forms. The fl1.2.32 antibody was raised against HIV-1 protease and cross-reacts with residues 36-46 of the protein (Lescar et al, 1997). A comparison of the free and peptide complexed Fab fl1.2.32 shows conformational changes in the long hypervariable regions L1 and H3, which are mobile in the free fragment.…”

Section: Cyclosporin a As A Model Antigenmentioning

confidence: 99%

Cyclosporin A as a model antigen: immunochemical and structural studies

Altschuh

2002

J of Molecular Recognition

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The immunosuppressant drug cyclosporin (Cs) A is a cyclic undecapeptide which has been used as a model antigen because structural information and a large number of analogs, modified at each of its 11 positions, were available. This review summarizes immunochemical and crystallographic studies of the interaction between the Fab of monoclonal antibody R45-45-11 and Cs. Three points are discussed: (1) the different conformations of CsA and the question of its biologically active form; (2) the Fab-CsA recognition mechanism; and (3) the relationship between structure and binding properties of CsA analogs.

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“…Our objective has been to study the activity and function of the enzyme, and to possibly aid in the design of alternative inhibitors targeted to regions other than the active site. Two HIV protease-inhibiting mAbs, F11.2.32 and 1696, have been selected and characterized (Lescar et al, 1996(Lescar et al, , 1997(Lescar et al, , 1999Rezacova et al, 2001Rezacova et al, , 2002. Although raised against HIV-1 PR, mAb 1696 inhibits the catalytic activity of both the HIV-1 and HIV-2 enzymes with inhibition constants of 0.6 and 1.5 nM, respectively (Lescar et al, 1999).…”

Section: Introductionmentioning

confidence: 99%