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  Director : BENTLEY Graham (bentley@pasteur.fr)



Research projects of the Unit of Structural Immunology are focussed on the structural study of antigenic recognition using the techniques of X-ray crystallography. They concern antibodies, T cell receptors and different antigenic molecules implicated in various bacterial, viral and parasite pathologies. Certain of our projects include molecules that are of interest for the development of vaccines and drugs. Particular emphasis is placed surface antigens from Plasmodium that are promising anti-malarial vaccine candidates. In many cases, the function of many Plasmodium antigens is poorly characterised, and we aim to contribute to understanding their biological role in the life cycle of the parasite by determining their 3-dimensional structure. Moreover, these structural results can be usefully exploited for vaccine development by providing a framework for analysing polymorhism and the distribution of important epitopes induced by these proteins when used as immunogens.



Structural Studies of Merozoite Surface Protein 1 (MSP1) from Plasmodium

(G.A.Bentley, G. Boulot, V. Chitarra, D. Verger, in collaboration with S. Longacre, Immunologie Moléculaire des Parasites I.P., and F. Nato, Ingénierie des Anticorps I.P.)

Surface proteins of the merozoite, the erythrocyte-invading form of Plasmodium, are promising anti-malaria vaccine candidates. In this regard, Merozoite Surface Protein 1 (MSP1) is one of the most widely studied of the Plasmodium surface antigens. This protein, which is implicated in the erythrocyte invasion process of the parasite, is subjected to several proteolytic cleavages during maturation of the merozoite. During the first phase, it is cleaved to yield four peptide fragments, of which the 42 kDa C-terminal fragment (MSP1-42) remains fixed to the merozoite membrane. During the second phase, occurring at the moment of erythrocyte invasion, MSP1-42 itself is cleaved to yield a polypeptide of molecular weight 11 kDa (MSP1-19). The latter cleavage is essential for erythrocyte invasion, although the mechanism of this process has yet to be elucidated. In order to understand the biological role of MSP1 in the infection of erythrocytes by Plasmodium, we are studying the structure of the recombinant fragments of this protein. Firstly, the structural comparison of MSP1-19 with MSP1-42 could help to explain the importance of the second cleavage step for the penetration of the red blood cell by the merozoite. Secondly, their 3-dimensional structure would give the spatial distribution of polymorphic (dimorphic) residues and the position of protecting epitopes, which is essential information for the optimal conception of candidate vaccine products. We have determined the structure of MSP1-19 from P. cynomolgi and MSP1-19 from P. falciparum as a complex with the Fab fragment of a specific monoclonal antibody.

Studies of the preS Antgenic Determinants of Hepatitis B Virus

(G.A. Bentley, F. Lema, J.P. Pizarro, M.M. Riottot, F. Saul, B. Vulliez-Le Normand)

The immune response to hepatitis B virus (HBV) is directed in large part against the viral surface antigen (HBsAg). The preS region of HbsAg (comprising segments preS1 and preS2) is very immunogenic and contains neutralising epitopes which play an important role in the elimination of the virus during infection. In addition, the segment preS1 plays a role in the attachment of the virus to the hepatocyte, the principle target cell of HBV. Characterisation of the conformation of this antigen and the 3-dimensional distribution of epitopes should improve our understanding of HBV and the mechanisms of immune protection afforded by these neutralising antibodies. Our studies are centred on the structural and immunochemical analysis of the preS region in order to characterise its antigenic properties.

Inhibition Studies of HIV Protease by Monoclonal Antibodies

(G. Bentley, V. Chitarra, M.M. Riottot, in collaboration with the laboratory of Dr. J. Sedlacek, Institute of Molecular Genetics, Czech Academy of Sciences, Prague)

The protease of Human Immunodeficiency Virus (HIV) is essential for the maturation and consequent infectivity of the virus because of its role in the enzymatic maturation of the viral polyprotein precursors, Gag/Pol and Gag. The object of this project is to study monoclonal antibodies that inhibit the proteolytic activity in order to analyse the dynamic behaviour of the enzyme. This year, we have continued our studies of the monoclonal antibody 1696 which inhibits the HIV protease by dissociation of the active homodimer into its inactive monomer subunits. Inhibition is achieved by the antibody binding to the N-terminal segment of the protease, a region that is important for the formation of the active homodimer. Although mAb 1696 was raised against the HIV-1 protease, it cross-reacts with the HIV-2 enzyme since it recognises is highly conserved epitope. We have determined the crystal structure of the recombinant Fv fragment of 1696 as a complex with the N-terminal peptide segment of HIV-1 protease as well as with the cross-reacting HIV-2 protease. Kinetic studies of protease inhibtion show that both mAb 1696 and the Fv 1696 that the inhibition constants are in the low nanomolar range for both the HIV-1 and HIV-2 enzymes.

Photo legends :

Figure 1. The epitope of MSP1-19 from Plasmodium falciparum recognised by a specfic monoclonal antibody. MSP1-19 is shown in blue with the epitope indicated in red. The antibody is shown in green.

Figure 2 ; The anti-HIV-1 protease monoclonal antibody, 1696, viewed from the side and from above the antigen-binding site. The antibody (shown in blue) recognises the N-terminal region of the HIV-2 enzyme (shown in red) as well as the corresponding region of the HIV-1 enzyme (shown in yellow).


puce Publications of the unit on Pasteur's references database


  Office staff Researchers Scientific trainees Other personnel

FEJT Françoise ffejt@pasteur.fr

BENTLEY Graham, researcher I.P. (bentley@pasteur.fr)

CHITARRA Véronique, researcher I.P. (chitarra@pasteur.fr)

LEMA Fernando, researcher I.P. (lema@pasteur.fr)

SAUL Frederick, researcher I.P. (fsaul@pasteur.fr)

PIZARRO Juan-Carlos, Ph. D. student

VERGER Denis, postdoc

BOULOT Ginette, engineer, CNRS (gboulot@pasteur.fr)

RIOTTOT Marie-Madeleine, engineer, CNRS (riottot@pasteur.fr)

VULLIEZ-LE NORMAND Brigitte, engineer I.P. (bvulliez@pasteur.fr)


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