Adnane Achour group

Cellular communication is achieved through the interactions of specialized receptor molecules at the cell surface and their ligands. Our research group uses X-ray crystallography and Small Angle X-ray Scattering (SAXS) to study receptor-ligand interactions, such as e.g. between T or NK cell receptors and Major Histocompatibility Complex (MHC) molecules, as well as bacterial adhesins.

All of our studies are complemented by a wide array of immunological assays as well as an extensive amount of biochemical techniques, including surface plasmon resonance and circular dichroism. By understanding the structural details of proteins, we can probe their function and potentially design artificial ligands that could modulate their function and activity.

The Achour research group is mainly localized within the Science for Life Laboratory in the north campus of the Karolinska Institutet.

Keywords: X-ray crystallography, cellular immunology, biochemistry, T cell receptor (TCR)-NK cell receptor (NKR)/MHC immunomodulation, pathogen-derived proteins, allergens

Members

Adil Duru, Hannes Uchtenhagen, Eva Allerbring, Tim Schulte, Inga Mueller, Elodie Maitrepierre, Adnane Achour.

Adnane Achour, Group Leader, Associate Professor. Phone: +46-8-524 862 16
Tatyana Sandalova, PhD, Senior Scientist
Tim Schulte, PhD, post-doctoral fellow
Eva Allerbring, PhD
Lara Mentlein, PhD student
Cecilia Mikaelsson, PhD student

Former PhD students of the research group

Hannes Uchtenhagen

Hannes defended his PhD thesis in 2013: "Elicitation and enhancement of T and B cell responses". During his PhD studies, Hannes successfully combined functional immunology with biochemistry and structural biology in order to address the possible enhancement of TCR responses by altered peptide ligands. Furthermore, he also determined the three-dimensional structure of the Fab fragment of an HIV-1-neutralizing antibody. Finally, his studies demonstrated the possibility to make use of stable SIV-derived gp140 trimers in order to induce potent cross-reactive HIV-1 neutralization.

More about the thesis

Adil Duru

Adil defended his PhD thesis in 2013: "MHC class I-restricted peptide-based immunomodulation of CD8+ T cells and NK cells". His studies addressed mainly how TCR responses can be modulated by altered peptide ligands.

More about the thesis

Samer Sourial

Samer defended his PhD thesis in 2005: "Functional studies on the interaction of immunoglobulins with HIV-2 envelope". The PhD project of Samer focused on molecular differences between the HIV-2-associated molecule gp125 and the HIV-1-derived gp120, trying to understand the role of the V3 region in gp125 for neutralization of HIV-2.

More about the thesis

Claudia Wagner (born Thilo)

Claudia defended her PhD thesis in 2007. "Immune evasion of human cytomegalovirus; Studies of UL18 and US2 function". The PhD project of Claudia focused on understanding the molecular basis underlying the function of two important CMV-derived proteins. Dr Claudia Wagner is now a post-doctoral fellow at Yale University, USA.

More about the thesis

Other former PhD students co-supervised by Adnane Achour

Melissa Norström

Melissa performed her PhD studies in the laboratory of Ass. Prof. Annika Karlsson (Karolinska Institutet). Melissa defended her PhD thesis in 2013: "Unifying viral evolution and immunological patterns to investigate risk of HIV-1 disease progression".

More about the thesis

Tolga Sütlü

Tolga performed his PhD studies in the laboratory of Ass. Prof. Evren Alici (Karolinska Institutet). Tolga defended his PhD thesis in 2013: "Expansion and genetic modification of human natural killer cells for adoptive immunotherapy of cancer".

More about the thesis

Monica Vilhelmsson

Monica performed her PhD studies in the laboratory of Prof. Annika Scheynius (Karolinska Institutet). We collaborated on the determination of the three-dimensional structures of specific allergens. Monica defended her PhD thesis in 2008: "Structural and functional studies of Malassezia Sympodialis-derived allergens".

More about the thesis

Alexander Rölle

Alexander performed his PhD studies in the laboratory of Prof. Klas Kärre (Karolinska Institutet). Alexander defended his PhD thesis in 2008: "Natural killer cell mediated recognition of herpesviruses  Mechanisms of viral immune escape".

More about the thesis

Arnaud Chêne

Arnaud performed his PhD studies in the laboratories of Prof. Mats Wahlgren and Assoc. Prof. Maria Teresa Bejarano (both at the Karolinska Institutet). Arnaud defended his PhD thesis in 2009: "Impact of malaria on B-cell homeostasis and Epstein-Barr virus reactivation  Endemic Burkitt´s lymphoma pathogenesis".

More about the thesis

Former members of the research group

Fabrice Neiers

Post-doctoral fellow in our laboratory in 2008-2010. Fabrice has determined the three-dimensional structures of Streptococcus pneumoniae-associated sortases. Fabrice Neiers is now an associated professor at Faculté de Pharmacie, Dijon, France.

Chaithanya Madhurantakam

Post-doctoral fellow in our laboratory in 2007-2009. Chiathanya has determined the crystal structure of the dog allergen Can f 2. He has also determined the crystal structure of MHC class I molecules in complex with post-translationally modified epitopes.

Pooja Anjali Mazumdar

Post-doctoral fellow in our laboratory in 2008-2009. Pooja has determined the crystal of MHC class I molecules in complex with neo-epitopes.

Daniel Badia-Martinez

Post-doctoral fellow in our laboratory in 2006-2008. Daniel determined the three-dimensional structure of several MHC class I molecules in complex with cancer-associated peptides. He has also been deeply involved in structural studies of the main cat allergen Fel d 1.

Liselotte Kaiser

Post-doctoral fellow in our laboratory in 2004-2005. Liselotte determined the crystal structure of the main cat allergen Fel d 1.

Projects

Development of MHC class I-binding altered peptides for vaccines

Using a combination of structural biology and immunology, our research group has defined a procedure that allows for the design of altered peptide ligands (APLs) that bind with high affinity to MHC-I ligands. The immunogenic APLs act as mimotopes of disease-associated non-immunogenic epitopes, and enhance the stability of MHC-I molecules. Importantly, these modified peptides conserve a structural conformation similar to the wild-type infection-derived or non-immunogenic tumor-associated peptides.

Studies performed within our laboratory demonstrate that the induced immunogenic CD8+ T cells cross-react with the original peptides, resulting in enhanced in vitro and in vivo responses. Studies of the functional and structural consequences of substitutions in APLs on CD8 responses directed towards melanoma, multiple myeloma and acute lymphoblastic leukemia tumor associated antigens are ongoing. The effects of similar modifications are also tested on modulation of recognition by natural killer (NK) cells.

Determination of the crystal structures of Streptococcus pneumoniae-associated virulence factors

Streptococcus pneumoniae (pneumococcus) is a major human pathogen and the leading cause of pneumoniae, bacteremia and meningitis in adults. The increasing number of antibiotic-resistant strains and the suboptimal clinical efficacy of available vaccines hamper control of this pathogen. In close collaboration with the research group of Prof. Birgitta Henriques-Normark and Staffan Normark, we are focusing on novel virulence-related pneumococcal proteins that could be used as potential targets for future drugs. The crystal structure of the protein sortase C, important for the formation of the pilus was determined.

See more pictures of crystals in the gallery

Determination of the crystal structures of main allergens

Finally, our research group has a strong interest in determining the crystal structures of allergens which provide important information regarding the initiation of allergy responses. In close collaboration with the research group of Assoc. Prof. Hans Grönlund, we have determined the crystal structures of several allergens including the major cat allergen Fel d 1 and the dog allergen Can f2. These three-dimensional structures are used as templates for the design of hypoallergenic variants and to identify main antibody epitopes.

Selected publications

Inflammation-associated nitrotyrosination affects TCR recognition through reduced stability and alteration of the molecular surface of the MHC complex.
Madhurantakam C, Duru A, Sandalova T, Webb J, Achour A
PLoS ONE 2012 ;7(3):e32805

Inflammation-associated nitrotyrosination affects TCR recognition through reduced stability and alteration of the molecular surface of the MHC complex.
Madhurantakam C, Duru A, Sandalova T, Webb J, Achour A
PLoS ONE 2012 ;7(3):e32805

Crystal structure of the HIV-2 neutralizing Fab fragment 7C8 with high specificity to the V3 region of gp125.
Uchtenhagen H, Friemann R, Raszewski G, Spetz A, Nilsson L, Achour A
PLoS ONE 2011 Apr;6(4):e18767

Crystal structure of the dog lipocalin allergen Can f 2: implications for cross-reactivity to the cat allergen Fel d 4.
Madhurantakam C, Nilsson O, Uchtenhagen H, Konradsen J, Saarne T, Högbom E, et al
J. Mol. Biol. 2010 Aug;401(1):68-83

Generation of neutralizing antibodies and divergence of SIVmac239 in cynomolgus macaques following short-term early antiretroviral therapy.
Ozkaya Sahin G, Bowles E, Parker J, Uchtenhagen H, Sheik-Khalil E, Taylor S, et al
PLoS Pathog. 2010 Sep;6(9):e1001084

Design of agonistic altered peptides for the robust induction of CTL directed towards H-2Db in complex with the melanoma-associated epitope gp100.
van Stipdonk M, Badia-Martinez D, Sluijter M, Offringa R, van Hall T, Achour A
Cancer Res. 2009 Oct;69(19):7784-92

Two crystal structures of pneumococcal pilus sortase C provide novel insights into catalysis and substrate specificity.
Neiers F, Madhurantakam C, Fälker S, Manzano C, Dessen A, Normark S, et al
J. Mol. Biol. 2009 Oct;393(3):704-16

Immune modulation by the human cytomegalovirus-encoded molecule UL18, a mystery yet to be solved.
Wagner C, Ljunggren H, Achour A
J. Immunol. 2008 Jan;180(1):19-24

Structural characterization of the tetrameric form of the major cat allergen Fel d 1.
Kaiser L, Velickovic T, Badia-Martinez D, Adedoyin J, Thunberg S, Hallén D, et al
J. Mol. Biol. 2007 Jul;370(4):714-27 

Structural elements underlying the high binding affinity of human cytomegalovirus UL18 to leukocyte immunoglobulin-like receptor-1.
Wagner C, Rölle A, Cosman D, Ljunggren H, Berndt K, Achour A
J. Mol. Biol. 2007 Oct;373(3):695-705

Dissection of the interaction of the human cytomegalovirus-derived US2 protein with major histocompatibility complex class I molecules: prominent role of a single arginine residue in human leukocyte antigen-A2.
Thilo C, Berglund P, Applequist S, Yewdell J, Ljunggren H, Achour A
J. Biol. Chem. 2006 Mar;281(13):8950-7

Structural basis of the differential stability and receptor specificity of H-2Db in complex with murine versus human beta2-microglobulin.
Achour A, Michaëlsson J, Harris R, Ljunggren H, Kärre K, Schneider G, et al
J. Mol. Biol. 2006 Feb;356(2):382-96

A structural basis for CD8+ T cell-dependent recognition of non-homologous peptide ligands: implications for molecular mimicry in autoreactivity.
Sandalova T, Michaëlsson J, Harris R, Odeberg J, Schneider G, Kärre K, et al
J. Biol. Chem. 2005 Jul;280(29):27069-75

Determination of structural principles underlying three different modes of lymphocytic choriomeningitis virus escape from CTL recognition.
Velloso L, Michaëlsson J, Ljunggren H, Schneider G, Achour A
J. Immunol. 2004 May;172(9):5504-11

The crystal structure of the major cat allergen Fel d 1, a member of the secretoglobin family.
Kaiser L, Grönlund H, Sandalova T, Ljunggren H, van Hage-Hamsten M, Achour A, et al
J. Biol. Chem. 2003 Sep;278(39):37730-5

A signal peptide derived from hsp60 binds HLA-E and interferes with CD94/NKG2A recognition.
Michaëlsson J, Teixeira de Matos C, Achour A, Lanier L, Kärre K, Söderström K
J. Exp. Med. 2002 Dec;196(11):1403-14

A structural basis for LCMV immune evasion: subversion of H-2D(b) and H-2K(b) presentation of gp33 revealed by comparative crystal structure.Analyses.
Achour A, Michaëlsson J, Harris R, Odeberg J, Grufman P, Sandberg J, et al
Immunity 2002 Dec;17(6):757-68

The crystal structure of H-2Dd MHC class I complexed with the HIV-1-derived peptide P18-I10 at 2.4 A resolution: implications for T cell and NK cell recognition.
Achour A, Persson K, Harris R, Sundbäck J, Sentman C, Lindqvist Y, et al
Immunity 1998 Aug;9(2):199-208

Gallery

Atomic visualization of the three-dimensional structures of proteins is essential for a complete understanding of the molecular basis underlying immune cell functions and development of infectious diseases. Here are some examples of our X-ray crystallography pictures.

 

 

 

Open positions

We always want to get in touch with talented potential coworkers. If you are interested in doing research within our group, as a degree project or as a researcher, please contact the group leader Adnane Achour.

Some useful links

Proteins:

PDB 

PDBe 

Expasy 

NCBI 

Protein CD DB 

Proteopedia 

ProMals3D 

DALI 

CLUSTPRO 

Pepsite 

Immunology:  

IMGT 

IEDB 

MHC-binding Predictor 

EpiJen 

SDAP – Allergens 

Crystallography:

 ESRF 

MaxLab 

DESY 

BESSY 

Uppsala SF 

XstalPred 

ISpyB (ESRF) 

Programs:

CCP4 

CCP4wiki 

PyMol 

CNS 

Mosflm 

XDS 

Phenix 

SHARP 

iMOSFLM 

Servers:

 DockBlaster 

DockBlaster 

Haddock 

RosettaDock 

Auto-Rickshaw 

Balbes 

PRODRG 

PISA 

TLSMD 

Kinari 

MolProbity 

I-Tasser 

Infectious Disease Medicine