RESUMEN
BACKGROUND: The soluble isoform of FcÉRI, the high-affinity IgE receptor (sFcεRI), is a protein of the IgE network with poorly defined functions. OBJECTIVE: To define cellular sources and signals that result in the production of human sFcεRI and study its in vivo functions. METHODS: FcεRI-transfected human cell lines (MelJuso), human monocyte-derived dendritic cells (moDCs), and murine bone marrow-derived mast cells (MC) were stimulated by FcεRI cross-linking and release of sFcεRI was analyzed (ELISA, Western Blot). Lysosomal-associated membrane protein 1 degranulation assays and human basophil activation tests (BATs) were used to study IgE-dependent activation. Recombinant sFcεRI (rsFcεRI) was used to assess its role in murine models of anaphylaxis with WT (wild-type) and IgE-/- (IgE-deficient) mice. RESULTS: Antigen-specific cross-linking of IgE-loaded FcÉRI on MelJuso cells that express the trimeric or tetrameric receptor isoform induced the production of sFcεRI. Using MCs and moDCs, we confirmed that IgE/FcÉRI activation induces sFcÉRI release. We demonstrated that generation of sFcÉRI requires Src phosphorylation and endo/lysosomal acidification. In experimental mouse models, sFcÉRI diminishes the severity of IgE-mediated anaphylaxis. BATs confirmed that, comparable to the anti-IgE monoclonal antibody omalizumab, sFcÉRI is an inhibitor of the human innate IgE effector axis, implying that sFcÉRI and omalizumab potentially inhibit each other in vivo. CONCLUSION: sFcÉRI is produced after antigen-specific IgE/FcÉRI-mediated activation signals and functions as an endogenous inhibitor of IgE loading to FcÉRI and IgE-mediated activation. Our results imply, therefore, that sFcÉRI contributes to a negative regulatory feedback loop that aims at preventing overshooting responses after IgE-mediated immune activation.
Asunto(s)
Inmunoglobulina E/inmunología , Inmunoglobulina E/metabolismo , Mastocitos/inmunología , Mastocitos/metabolismo , Receptores de IgE/metabolismo , Animales , Basófilos/inmunología , Basófilos/metabolismo , Biomarcadores , Degranulación de la Célula/inmunología , Línea Celular Tumoral , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Endosomas/metabolismo , Humanos , Inmunoglobulina E/química , Lisosomas/metabolismo , Ratones , Ratones Noqueados , Unión Proteica , Isoformas de Proteínas , Multimerización de Proteína , Receptores de IgE/químicaRESUMEN
We have solved the structure of the human high affinity IgE receptor, Fc epsilon RI alpha, in six different crystal forms, showing the structure in 15 different chemical environments. This database of structures shows no change in the overall shape of the molecule, as the angle between domains 1 and 2 (D1 and D2) varies little across the ensemble. However, the receptor has local conformational variability in the C' strand of D2 and in the BC loop of D1. In every crystal form, a residue inserts between tryptophan residues 87 and 110, mimicking the position of a proline from the IgE ligand. The different crystal forms reveal a distribution of carbohydrates lining the front and back surfaces of the structure. An analysis of crystal contacts in the different forms indicates regions where the molecule interacts with other proteins, and reveals a potential new binding site distal to the IgE binding site. The results of this study point to new directions for the design of molecules to inhibit the interaction of Fc epsilon RI alpha with its natural ligand and thus to prevent a primary step in the allergic response.
Asunto(s)
Receptores de IgE/química , Receptores de IgE/metabolismo , Sitios de Unión , Metabolismo de los Hidratos de Carbono , Cristalización , Cristalografía por Rayos X , Bases de Datos como Asunto , Diseño de Fármacos , Glicoproteínas/química , Glicoproteínas/metabolismo , Humanos , Inmunoglobulina E/química , Inmunoglobulina E/metabolismo , Cadenas Pesadas de Inmunoglobulina/química , Cadenas Pesadas de Inmunoglobulina/metabolismo , Ligandos , Modelos Moleculares , Unión Proteica , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , TermodinámicaRESUMEN
Peptides derived from heptad repeat regions adjacent to the fusion peptide and transmembrane domains of many viral fusion proteins form stable helical bundles and inhibit fusion specifically. Paramyxovirus SV5 fusion (F) protein-mediated fusion and its inhibition by the peptides N-1 and C-1 were analyzed. The temperature dependence of fusion by F suggests that thermal energy, destabilizing proline residues and receptor binding by the hemagglutinin-neuraminidase (HN) protein collectively contribute to F activation from a metastable native state. F-mediated fusion was reversibly arrested by low temperature or membrane-incorporated lipids, and the resulting F intermediates were characterized. N-1 inhibited an earlier F intermediate than C-1. Co-expression of HN with F lowered the temperature required to attain the N-1-inhibited intermediate, consistent with HN binding to its receptor stimulating a conformational change in F. C-1 bound and inhibited an intermediate of F that could be detected until a point directly preceding membrane merger. The data are consistent with C-1 binding a pre-hairpin intermediate of F and with helical bundle formation being coupled directly to membrane fusion.
Asunto(s)
Fusión de Membrana/fisiología , Respirovirus/fisiología , Proteínas Virales de Fusión/metabolismo , Animales , Línea Celular , Chlorocebus aethiops , Expresión Génica , Proteína HN/genética , Proteína HN/metabolismo , Humanos , Respirovirus/genética , Respirovirus/metabolismo , Temperatura , Células Vero , Proteínas Virales de Fusión/genéticaRESUMEN
IgE antibodies mediate antiparasitic immune responses and the inflammatory reactions of allergy and asthma. We have solved the crystal structure of the human IgE-Fc Cepsilon3-Cepsilon4 domains to 2.3 A resolution. The structure reveals a large rearrangement of the N-terminal Cepsilon3 domains when compared to related IgG-Fc structures and to the IgE-Fc bound to its high-affinity receptor, FcepsilonRI. The IgE-Fc adopts a more compact, closed configuration that places the two Cepsilon3 domains in close proximity, decreases the size of the interdomain cavity, and obscures part of the FcepsilonRI binding site. IgE-Fc conformational flexibility may be required for interactions with two distinct IgE receptors, and the structure suggests strategies for the design of therapeutic compounds for the treatment of IgE-mediated diseases.
Asunto(s)
Especificidad de Anticuerpos , Sitios de Unión de Anticuerpos , Regiones Constantes de Inmunoglobulina/química , Inmunoglobulina E/química , Fragmentos Fc de Inmunoglobulinas/química , Conformación de Carbohidratos , Simulación por Computador , Cristalografía por Rayos X , Disacáridos/química , Disacáridos/inmunología , Disacáridos/metabolismo , Humanos , Regiones Constantes de Inmunoglobulina/metabolismo , Inmunoglobulina E/metabolismo , Fragmentos Fc de Inmunoglobulinas/metabolismo , Modelos Moleculares , Oligosacáridos/química , Oligosacáridos/inmunología , Oligosacáridos/metabolismo , Conformación Proteica , Estructura Terciaria de Proteína , Receptores de IgE/química , Receptores de IgE/metabolismo , Relación Estructura-ActividadRESUMEN
The initiation of immunoglobulin-E (IgE)-mediated allergic responses requires the binding of IgE antibody to its high-affinity receptor, Fc epsilonRI. Crosslinking of Fc epsilonRI initiates an intracellular signal transduction cascade that triggers the release of mediators of the allergic response. The interaction of the crystallizable fragment (Fc) of IgE (IgE-Fc) with Fc epsilonRI is a key recognition event of this process and involves the extracellular domains of the Fc epsilonRI alpha-chain. To understand the structural basis for this interaction, we have solved the crystal structure of the human IgE-Fc-Fc epsilonRI alpha complex to 3.5-A resolution. The crystal structure reveals that one receptor binds one dimeric IgE-Fc molecule asymmetrically through interactions at two sites, each involving one C epsilon3 domain of the IgE-Fc. The interaction of one receptor with the IgE-Fc blocks the binding of a second receptor, and features of this interaction are conserved in other members of the Fc receptor family. The structure suggests new approaches to inhibiting the binding of IgE to Fc epsilonRI for the treatment of allergy and asthma.
Asunto(s)
Inmunoglobulina E/química , Fragmentos de Inmunoglobulinas/química , Receptores de IgE/química , Especificidad de Anticuerpos , Cristalografía por Rayos X , Humanos , Inmunoglobulina E/genética , Inmunoglobulina E/inmunología , Inmunoglobulina E/metabolismo , Fragmentos de Inmunoglobulinas/genética , Fragmentos de Inmunoglobulinas/metabolismo , Sustancias Macromoleculares , Modelos Moleculares , Mutación , Unión Proteica , Conformación Proteica , Receptores de IgE/genética , Receptores de IgE/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismoRESUMEN
Fusion proteins from a group of widely disparate viruses, including the paramyxovirus F protein, the HIV and SIV gp160 proteins, the retroviral Env protein, the Ebola virus Gp, and the influenza virus haemagglutinin, share a number of common features. All contain multiple glycosylation sites, and must be trimeric and undergo proteolytic cleavage to be fusogenically active. Subsequent to proteolytic cleavage, the subunit containing the transmembrane domain in each case has an extremely hydrophobic region, termed the fusion peptide, or at near its newly generated N-terminus. In addition, all of these viral fusion proteins have 4-3 heptad repeat sequences near both the fusion peptide and the transmembrane domain. These regions have been demonstrated from a tight complex, in which the N-terminal heptad repeat forms a trimeric-coiled coil, with the C-terminal heptad repeat forming helical regions that buttress the coiled-coil in an anti-parallel manner. The significance of each of these structural elements in the processing and function of these viral fusion proteins is discussed.
Asunto(s)
Fusión de Membrana/fisiología , Proteínas Virales de Fusión/química , Proteínas Virales de Fusión/fisiología , Estructura Terciaria de ProteínaRESUMEN
Paramyxoviruses are responsible for significant human mortality and disease worldwide, but the molecular mechanisms underlying their entry into host cells remain poorly understood. We have solved the crystal structure of a fragment of the simian parainfluenza virus 5 fusion protein (SV5 F), revealing a 96 A long coiled coil surrounded by three antiparallel helices. This structure places the fusion and transmembrane anchor of SV5 F in close proximity with a large intervening domain at the opposite end of the coiled coil. Six amino acids, potentially part of the fusion peptide, form a segment of the central coiled coil, suggesting that this structure extends into the membrane. Deletion mutants of SV5 F indicate that putative flexible tethers between the coiled coil and the viral membrane are dispensable for fusion. The lack of flexible tethers may couple a final conformational change in the F protein directly to the fusion of two bilayers.
Asunto(s)
Fusión de Membrana , Respirovirus/metabolismo , Proteínas Virales de Fusión/química , Secuencia de Aminoácidos , Secuencia Conservada , Cristalización , Dimerización , Electrones , Enlace de Hidrógeno , Iones , Modelos Biológicos , Modelos Moleculares , Datos de Secuencia Molecular , Fragmentos de Péptidos/química , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Unión Proteica , Conformación Proteica , Estructura Secundaria de Proteína , Respirovirus/química , Respirovirus/genética , Eliminación de Secuencia , Proteínas Virales de Fusión/genética , Proteínas Virales de Fusión/metabolismoRESUMEN
Streptococcal superantigen (SSA) is a 28,000 Mr toxin originally isolated from a pathogenic strain of Streptococcus pyogenes that has 60% sequence identity with staphylococcal enterotoxin B (SEB). SSA and SEB, however, do not compete for binding on the surfaces of cells expressing MHC class II molecules. This behavior had been ascribed to SSA and SEB binding to distinct sites on, or different subsets of, HLA-DR molecules. Here we demonstrate that SSA binds predominantly to HLA-DQ, rather than to HLA-DR molecules, and present the crystal structure of SSA at 1.85 A resolution. These data provide a structural basis for interpreting the interaction of SSA with HLA-DQ molecules as well as a foundation for understanding bacterial superantigen affinities for distinct MHC isotypes.
Asunto(s)
Antígenos Bacterianos/inmunología , Antígenos HLA-DQ/inmunología , Streptococcus pyogenes/inmunología , Secuencia de Aminoácidos , Antígenos Bacterianos/química , Cristalografía por Rayos X , Antígenos HLA-DQ/química , Modelos Moleculares , Datos de Secuencia Molecular , Estructura Molecular , Proteínas Recombinantes/química , Proteínas Recombinantes/inmunología , Homología de Secuencia de AminoácidoRESUMEN
To characterize the importance of a highly conserved region of the class II beta chain, we introduced an amino acid substitution that is predicted to eliminate a hydrogen bond formed between the class II molecule and peptide. We expressed the mutated beta chain with a wild-type alpha chain in a murine L cell by gene transfection. The mutant class II molecule (81betaH-) assembles normally in the endoplasmic reticulum and transits the Golgi complex. When invariant chain (Ii) is coexpressed with 81betaH-, the class II-Ii complex is degraded in the endosomes. Expression of 81betaH- in the absence of Ii results in a cell surface expressed molecule that is susceptible to proteolysis, a condition reversed by incubation with a peptide known to associate with 81betaH-. We propose that 81betaH- is protease sensitive because it is unable to productively associate with most peptides, including classII-associated invariant chain peptides. This model is supported by our data demonstrating protease sensitivity of peptide-free wild-type I-Ad molecules. Collectively, our results suggest both that the hydrogen bonds formed between the class II molecule and peptide are important for the integrity and stability of the complex, and that empty class II molecules are protease sensitive and degraded in endosomes. One function of DM may be to insure continuous groove occupancy of the class II molecule.
Asunto(s)
Antígenos de Histocompatibilidad Clase II , Sustitución de Aminoácidos , Animales , Línea Celular , Genes MHC Clase II , Antígenos de Histocompatibilidad Clase II/química , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/metabolismo , Hidrógeno , Ratones , Mutación , Conformación Proteica , Relación Estructura-ActividadRESUMEN
Allergic responses result from the activation of mast cells by the human high-affinity IgE receptor. IgE-mediated allergic reactions may develop to a variety of environmental compounds, but the initiation of a response requires the binding of IgE to its high-affinity receptor. We have solved the X-ray crystal structure of the antibody-binding domains of the human IgE receptor at 2.4 A resolution. The structure reveals a highly bent arrangement of immunoglobulin domains that form an extended convex surface of interaction with IgE. A prominent loop that confers specificity for IgE molecules extends from the receptor surface near an unusual arrangement of four exposed tryptophans. The crystal structure of the IgE receptor provides a foundation for the development of new therapeutic approaches to allergy treatment.
Asunto(s)
Receptores de IgE/química , Secuencia de Aminoácidos , Animales , Sitios de Unión , Línea Celular , Cristalización , Cristalografía por Rayos X/métodos , Glicosilación , Humanos , Inmunoglobulina E/metabolismo , Modelos Moleculares , Datos de Secuencia Molecular , Peso Molecular , Conformación Proteica , Estructura Terciaria de Proteína , Receptores de IgE/genética , Receptores de IgE/aislamiento & purificación , Receptores de IgE/metabolismo , Proteínas Recombinantes/química , Alineación de Secuencia , Solubilidad , TriptófanoRESUMEN
The structure of a ternary complex formed between a T-cell receptor, a major histocompatibility complex (MHC) protein and a viral peptide provides new insights into the cellular immune response. The results provide a molecular basis for understanding the development of T cells and the reactions leading to transplant rejection and autoimmunity.
Asunto(s)
Productos del Gen tax/química , Antígeno HLA-A2/química , Conformación Proteica , Receptores de Antígenos de Linfocitos T alfa-beta/química , Productos del Gen tax/inmunología , Productos del Gen tax/metabolismo , Antígeno HLA-A2/inmunología , Antígeno HLA-A2/metabolismo , Humanos , Recién Nacido , Sustancias Macromoleculares , Modelos Moleculares , Unión Proteica , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Especificidad por SustratoRESUMEN
The structure of the human major histocompatibility complex (MHC) class II molecule HLA-DR1 derived from the human lymphoblastoid cell line LG-2 has been determined in a complex with the Staphylococcus aureus enterotoxin B superantigen. The HLA-DR1 molecule contains a mixture of endogenous peptides derived from cellular or serum proteins bound in the antigen-binding site, which copurify with the class II molecule. Continuous electron density for 13 amino acid residues is observed in the MHC peptide-binding site, suggesting that this is the core length of peptide that forms common interactions with the MHC molecule. Electron density is also observed for side chains of the endogenous peptides. The electron density corresponding to peptide side chains that interact with the DR1-binding site is more clearly defined than the electron density that extends out of the binding site. The regions of the endogenous peptides that interact with DRI are therefore either more restricted in conformation or sequence than the peptide side chains or amino acids that project out of the peptide-binding site. The hydrogen-bond interactions and conformation of a peptide model built into the electron density are similar to other HLA-DR-peptide structures. The bound peptides assume a regular conformation that is similar to a polyproline type II helix. The side-chain pockets and conserved asparagine residues of the DR1 molecule are well-positioned to interact with peptides in the polyproline type II conformation and may restrict the range of acceptable peptide conformations.
Asunto(s)
Antígeno HLA-DR1/química , Péptidos/química , Secuencia de Aminoácidos , Cristalografía , Humanos , Enlace de Hidrógeno , Modelos Moleculares , Datos de Secuencia Molecular , Unión Proteica , Conformación ProteicaRESUMEN
The MHC class II molecules, expressed by antigen presenting cells, are heterodimers composed of an alpha and a beta chain, which function to present processed antigen to helper T cells. The human MHC class II molecules, HLA-DR1 and HLA-DR3, crystallized not as monomers, but rather dimers of alpha beta heterodimers. The 'dimer of dimers' or 'superdimer' structure led to speculation that the binding of T-cell receptors to monomeric class II molecules on the antigen presenting cell surface may affect dimerization and thus initiate signaling both in the T cell and in the antigen presenting cell. Recent biochemical analyses of the mouse MHC class II Ek molecule provide evidence that dimers of class II heterodimers form in the absence of T cells. Although such dimers were shown to augment T-cell stimulation, the dimerization of class II molecules alone is unlikely to initiate signal transduction. However, dimers may be important in stabilizing weak T-cell receptor/CD4/class II interactions, allowing further multimerization of such complexes, leading to signaling.
Asunto(s)
Presentación de Antígeno , Antígenos de Histocompatibilidad Clase II/química , Transducción de Señal , Animales , Linfocitos B/inmunología , Cristalografía por Rayos X , Antígenos de Histocompatibilidad Clase II/fisiología , Humanos , Ratones , Modelos Moleculares , Conformación Proteica , Linfocitos T/inmunología , Linfocitos T Colaboradores-Inductores/fisiologíaRESUMEN
The three-dimensional structure of the extracellular region of a 60 kDa class II major histocompatibility glycoprotein, HLA-DR1, was determined to 3.3 A by X-ray crystallography using three crystal forms, each containing two molecules per asymmetric unit. Phases were initially determined to 4.2 A using two crystal forms both containing DR1 from human lymphocytes complexed with a mixture of endogenous peptides. One of these crystal forms also contained a 28 kDa superantigen, Staphylococcus aureus enterotoxin B (SEB), bound to each DR1 molecule. Single-isomorphous replacement phasing followed by iterative two- and fourfold non-crystallographic real-space averaging between the two crystal forms resulted in 4.2 A resolution electron-density maps from which the paths of the polypeptides could be traced. Cryocrystallography and synchrotron radiation were then used to extend the resolution to 3.3 A for the two lymphocyte-derived crystal forms and for a third crystal form grown from DR1 produced in insect cells and complexed in vitro with a specific antigenic peptide. Iterative sixfold non-crystallographic real-space averaging resulted in an electron- density map into which 340 of 371 residues could be fit unambiguously. Crystal contacts and the existence of a parallel dimer of the DR1 alphabeta heterodimer in the three crystal forms are discussed.
RESUMEN
Superantigens bind to major histocompatibility complex class II molecules on antigen-presenting cells and stimulate T cells. Staphylococcus aureus enterotoxin B (SEB) and toxic shock syndrome toxin-1 (TSST-1) bind to the same region of human lymphocyte antigen (HLA)-DR1 but do not compete with each other, which indicates that they bind to different subsets of DR1 molecules. Here, a mutation in the peptide-binding groove disrupted the SEB and TSST-1 binding sites, which suggests that peptides can influence the interaction with bacterial toxins. In support of this, the expression of the DR1 molecule in various cell types differentially affected the binding of these toxins.
Asunto(s)
Toxinas Bacterianas , Enterotoxinas/metabolismo , Antígeno HLA-DR1/metabolismo , Staphylococcus aureus , Superantígenos/metabolismo , Linfocitos T/inmunología , Animales , Presentación de Antígeno , Sitios de Unión , Unión Competitiva , Línea Celular , Enterotoxinas/química , Antígeno HLA-DR1/química , Antígeno HLA-DR1/genética , Células HeLa , Humanos , Hibridomas , Ratones , Mutación , Estructura Secundaria de Proteína , Superantígenos/químicaRESUMEN
The structure of a bacterial superantigen, Staphylococcus aureus enterotoxin B, bound to a human class II histocompatibility complex molecule (HLA-DR1) has been determined by X-ray crystallography. The superantigen binds as an intact protein outside the conventional peptide antigen-binding site of the class II major histocompatibility complex (MHC) molecule. No large conformational changes occur upon complex formation in either the DR1 or the enterotoxin B molecules. The structure of the complex helps explain how different class II molecules and superantigens associate and suggests a model for ternary complex formation with the T-cell antigen receptor (TCR), in which unconventional TCR-MHC contacts are possible.
Asunto(s)
Enterotoxinas/química , Antígeno HLA-DR1/química , Superantígenos/química , Secuencia de Aminoácidos , Animales , Cristalografía por Rayos X , Enterotoxinas/inmunología , Humanos , Sustancias Macromoleculares , Ratones , Modelos Moleculares , Datos de Secuencia Molecular , Receptores de Antígenos de Linfocitos T/metabolismo , Staphylococcus aureus/inmunología , Superantígenos/inmunologíaRESUMEN
An influenza virus peptide binds to HLA-DR1 in an extended conformation with a pronounced twist. Thirty-five per cent of the peptide surface is accessible to solvent and potentially available for interaction with the antigen receptor on T cells. Pockets in the peptide-binding site accommodate five of the thirteen side chains of the bound peptide, and explain the peptide specificity of HLA-DR1. Twelve hydrogen bonds between conserved HLA-DR1 residues and the main chain of the peptide provide a universal mode of peptide binding, distinct from the strategy used by class I histocompatibility proteins.
Asunto(s)
Antígeno HLA-DR1/química , Hemaglutininas Virales/química , Hemaglutininas/química , Fragmentos de Péptidos/química , Secuencia de Aminoácidos , Sitios de Unión , Cristalografía por Rayos X , Antígeno HLA-DR1/metabolismo , Glicoproteínas Hemaglutininas del Virus de la Influenza , Humanos , Enlace de Hidrógeno , Modelos Moleculares , Datos de Secuencia Molecular , Unión Proteica , Conformación Proteica , Receptores de Antígenos de Linfocitos T/metabolismoRESUMEN
Coordinates from x-ray structures of HLA-A*6801, HLA-A*0201, and HLA-B*2705 were analyzed to examine the basis for their selectivity in peptide binding. The pocket that binds the side chain of the peptide's second amino acid residue (P2 residue) shows a preference for Val, Leu, and Arg in these three HLA subtypes, respectively. The Arg-specific pocket of HLA-B*2705 differs markedly from those of HLA-A*0201 and HLA-A*6801, as a result of numerous differences in the side chains that form the pocket's surface. The cause of the specificity differences between HLA-A*0201 and HLA-A*6801 is more subtle and depends both on a change in conformation of pocket residue Val-67 and on a sequence difference at residue 9. The Val-67 conformational change appears to be caused by a shift in the position of the alpha 1-domain alpha-helix relative to the beta-sheet in the cleft and may, in fact, depend on amino acid differences remote from the P2 pocket. Analysis of the stereochemistry of the P2 side chain interacting with its binding pocket permits an estimate to be made of its contribution to the free-energy change of peptide binding.
Asunto(s)
Antígenos HLA-A/química , Antígenos HLA-B/química , Conformación Proteica , Estructura Secundaria de Proteína , Secuencia de Aminoácidos , Sitios de Unión , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Relación Estructura-Actividad , Valina , Difracción de Rayos XRESUMEN
The three-dimensional structure of the class II histocompatibility glycoprotein HLA-DR1 from human B-cell membranes has been determined by X-ray crystallography and is similar to that of class I HLA. Peptides are bound in an extended conformation that projects from both ends of an 'open-ended' antigen-binding groove. A prominent non-polar pocket into which an 'anchoring' peptide side chain fits is near one end of the binding groove. A dimer of the class II alpha beta heterodimers is seen in the crystal forms of HLA-DR1, suggesting class II HLA dimerization as a mechanism for initiating the cytoplasmic signalling events in T-cell activation.