Structural Dynamics of the Lipid Antigen-Binding Site of CD1d Protein

CD1 molecules present lipid antigens to T-cells in early stages of immune responses. Whereas CD1‒lipid‒T-cell receptors interactions are reasonably understood, molecular details on initial trafficking and loading of lipids onto CD1 proteins are less complete. We present a molecular dynamics (MD) study of human CD1d, the isotype that activates iNKT cells. MD simulations and calculations of properties and Poisson-Boltzmann electrostatic potentials were used to explore the dynamics of the antigen-binding domain of the apo-form, CD1d complexes with three lipid–antigens that activate iNKT cells and CD1d complex with GM2AP, a protein that assists lipid loading onto CD1 molecules in endosomes/lysosomes. The study was done at pH 7 and 4.5, values representative of strongly acidic environments in endosomal compartments. Our findings revealed dynamic features of the entrance to the hydrophobic channels of CD1d modulated by two α helices with sensitivity to the type of lipid. We also found lipid- and pH-dependent dynamic changes in three exposed tryptophans unique to CD1d among the five human CD1 isotypes. On the basis of modelled structures, our data also revealed external effects produced by the helper protein GM2AP only when it interacts in its open form, thus suggesting that the own assistant protein also adapts conformation to association with CD1d.

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Dynamic plasticity of the lipid antigen-binding site of CD1d is crucially favoured by acidic pH and helper proteins

Scientific Reports ◽

10.1038/s41598-020-62833-y ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Bruno Cuevas-Zuviría ◽

Marina Mínguez-Toral ◽

Araceli Díaz-Perales ◽

María Garrido-Arandia ◽

Luis F. Pacios

Keyword(s):

Binding Site ◽

Antigen Binding ◽

Acidic Ph ◽

Antigen Binding Site ◽

Lipid Antigen ◽

Dynamic Plasticity

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Structural determination of lipid antigens captured at the CD1d–T-cell receptor interface

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1705882114 ◽

2017 ◽

Vol 114 (31) ◽

pp. 8348-8353 ◽

Cited By ~ 17

Author(s):

Patrick J. Brennan ◽

Tan-Yun Cheng ◽

Daniel G. Pellicci ◽

Gerald F. M. Watts ◽

Natacha Veerapen ◽

...

Keyword(s):

T Cell ◽

Cell Receptor ◽

Sterile Inflammation ◽

Inkt Cells ◽

Lipid Antigens ◽

Lipid Antigen ◽

Specific Antigens ◽

Fragmentation Patterns ◽

Endogenous Lipids

Glycolipid antigens recognized by αβ T-cell receptors (TCRs) drive the activation of invariant natural killer T (iNKT) cells, a specialized subset of innate T lymphocytes. Glycolipids with α-linked anomeric carbohydrates have been identified as potent microbial lipid antigens for iNKT cells, and their unusual α-anomeric linkage has been thought to define a “foreign” lipid antigen motif. However, mammals use endogenous lipids to select iNKT cells, and there is compelling evidence for iNKT cell responses in various types of sterile inflammation. The nature of endogenous or environmental lipid antigens encountered by iNKT cells is not well defined. Here, we sought to identify lipid antigens in cow’s milk, a prominent part of the human diet. We developed a method to directly capture lipid antigens within CD1d–lipid–TCR complexes, while excluding CD1d bound to nonantigenic lipids, followed by direct biochemical analysis of the lipid antigens trapped at the TCR–CD1d interface. The specific antigens captured by this “TCR trap” method were identified as α-linked monohexosylceramides by mass spectrometry fragmentation patterns that distinguished α- from β-anomeric monohexosylceramides. These data provide direct biochemical evidence for α-linked lipid antigens from a common dietary source.

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Faculty Opinions recommendation of Variants of the antibody herceptin that interact with HER2 and VEGF at the antigen binding site.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1158476.618775 ◽

2009 ◽

Author(s):

Peter Colman ◽

Douglas Fairlie

Keyword(s):

Binding Site ◽

Antigen Binding ◽

Antigen Binding Site

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The mycoplasma surface proteins MIB and MIP promote the dissociation of the antibody-antigen interaction

Science Advances ◽

10.1126/sciadv.abf2403 ◽

2021 ◽

Vol 7 (10) ◽

pp. eabf2403

Author(s):

Pierre Nottelet ◽

Laure Bataille ◽

Geraldine Gourgues ◽

Robin Anger ◽

Carole Lartigue ◽

...

Keyword(s):

Surface Proteins ◽

Mycoplasma Species ◽

Antigen Binding ◽

Antigen Binding Site ◽

Fab Fragment ◽

Cryo Electron Microscopy ◽

Antigen Complex ◽

Antigen Interaction ◽

Immunoglobulin Binding

Mycoplasma immunoglobulin binding (MIB) and mycoplasma immunoglobulin protease (MIP) are surface proteins found in the majority of mycoplasma species, acting sequentially to capture antibodies and cleave off their VH domains. Cryo–electron microscopy structures show how MIB and MIP bind to a Fab fragment in a “hug of death” mechanism. As a result, the orientation of the VL and VH domains is twisted out of alignment, disrupting the antigen binding site. We also show that MIB-MIP has the ability to promote the dissociation of the antibody-antigen complex. This system is functional in cells and protects mycoplasmas from antibody-mediated agglutination. These results highlight the key role of the MIB-MIP system in immunity evasion by mycoplasmas through an unprecedented mechanism, and open exciting perspectives to use these proteins as potential tools in the antibody field.

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Uncommon structural motifs dominate the antigen binding site in human autoantibodies reactive with basement membrane collagen

Molecular Immunology ◽

10.1016/j.molimm.2016.07.004 ◽

2016 ◽

Vol 76 ◽

pp. 123-133 ◽

Cited By ~ 1

Author(s):

Mary H. Foster ◽

Elizabeth S. Buckley ◽

Benny J. Chen ◽

Kwan-Ki Hwang ◽

Amy G. Clark

Keyword(s):

Basement Membrane ◽

Binding Site ◽

Antigen Binding ◽

Antigen Binding Site ◽

Structural Motifs ◽

Basement Membrane Collagen ◽

Membrane Collagen

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A shared idiotype among human anti-Ro/SSA autoantibodies.

Journal of Experimental Medicine ◽

10.1084/jem.169.5.1583 ◽

1989 ◽

Vol 169 (5) ◽

pp. 1583-1588 ◽

Cited By ~ 5

Author(s):

K K Gaither ◽

J B Harley

Keyword(s):

Binding Site ◽

Heart Block ◽

Congenital Heart ◽

Congenital Heart Block ◽

Antigen Binding ◽

Normal Donor ◽

Neonatal Lupus ◽

Antigen Binding Site ◽

Fine Specificity ◽

Low Level

Idiotypes and antiidiotypes are thought to be important immune regulators and have provided clues for the origin and pathogenicity of autoantibodies. Many lupus and Sjögren's syndrome patients, as well as most neonatal lupus infants with congenital heart block or dermatitis, have antibodies to the ribonucleoprotein Ro/SSA, which is one of a group of RNA-protein autoantigens commonly found in human lupus sera. To characterize the fine specificity of anti-Ro/SSA antibodies, a rabbit antidiotypic serum was prepared against polyclonal affinity purified anti-Ro/SSA F(ab')2. The resulting antiidiotype, anti-Id-Rol, is specific for the F(ab')2 fraction of the anti-Ro/SSA immunogen and its binding to anti-Ro/SSA is inhibited by purified Ro/SSA. These data indicate that the Id-Rol epitope on anti-Ro/SSA is associated with the antigen binding site of these same antibodies. The Id-Rol idiotype was present by ELISA in 3 of 12 additional anti-Ro/SSA preparations from precipitin-positive donor sera and in anti-Ro/SSA from one normal donor with low level antibody. This is the first shared idiotype to be found in the human autoantibodies binding to this RNA-protein antigen. Idiotypic differences between anti-Ro/SSA autoantibodies have the potential to explain the variation in pathologic associations found in individuals who develop this autoantibody specificity.

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Binding Affinities of Sanggenon Derivatives as PTP1B Inhibitors; Using Molecular Dynamics and Free Energy Calculations

10.21203/rs.3.rs-598375/v1 ◽

2021 ◽

Author(s):

Safak OZHAN KOCAKAYA

Keyword(s):

Molecular Dynamics ◽

Free Energy ◽

Tyrosine Phosphatase ◽

Decomposition Analysis ◽

Md Simulations ◽

Free Energy Calculations ◽

Energy Decomposition Analysis ◽

Free Energy Decomposition ◽

Poisson Boltzmann ◽

Ptp1b Inhibitors

Abstract Recently, protein tyrosine phosphatase 1B (PTP1B) inhibitors have become the frontier as possible targeting for anti-cancer and antidiabetic drugs. The contemporary observe represents a pc assisted version to investigate the importance of precise residues within the binding web site of PTP1B with numerous Sanggenon derivatives remoted from nature. Molecular dynamics (MD) simulations were performed to estimate the dynamics of the complexes, and absolute binding unfastened energies have been calculated with exclusive additives, and carried out through the usage of the Molecular Mechanics-Poisson-Boltzmann floor region (MM-PB/SA) and Generalized Born surface vicinity (MM-GB/SA) strategies. The effects show that the expected free energies of the complexes are normally constant with the available experimental statistics. MM/GBSA free energy decomposition analysis shows that the residues Asp29, Arg24, Met258, and , Arg254 in the second active site in PTP1B are crucial for the excessive selectivity of the inhibitors.

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