In the last four years, the atomic structures of more than a half-dozen of the intercellular recognition complexes, formed by alpha beta T cell receptors ( alpha beta TCR) on cytotoxic T lymphocytes ...(CTL) or T helper cells and MHC/peptide complexes on antigen presenting cells, have been visualized by X-ray crystallography. These molecular complexes are the common recognition component in a diverse set of cell-cell encounters that activate the T cell receptor both during development of the repertoire of T cells within an individual organism (positive selection; negative selection; peripheral survival) and during the control (T helper) and effector stages (T killer) of an immune response. In the adaptive immune response, antigens are recognized by hypervariable molecules, antibodies or T cell receptors, which are expressed with sufficiently diverse structures to be able to recognize any protein antigen. Antibodies can bind to any part of the surface of a protein antigen. The receptors on T cells, however, are restricted to sensing the presence of protein antigens by binding to short peptides from the antigens that are presented on the surface of other cells bound to class I or class II molecules of the major histocompatibility complex (MHC). The crystallographic studies of TCR/peptide/MHC complexes have shown examples of viral antigen recognition, agonist and antagonist ligand recognition, and the allorecognition of graft rejection. Some induced fitting at the TCR interface is observed upon peptide/MHC binding, but no global conformational change has been observed that could initiate a signal or determine the different signals associated with agonist and antagonist ligands. All TCRs studied have been found to bind to peptide/MHC complexes in a similar way, positioned across the MHC/peptide surface at an angle between 45 degree and 80 degree . This similarity in binding mode is apparently achieved without using conserved contacts which may suggest its importance for initiating signals within T cells.
The membrane fusion potential of influenza HA, like many viral membrane-fusion glycoproteins, is generated by proteolytic cleavage of a biosynthetic precursor. The three-dimensional structure of ...ectodomain of the precursor HA0 has been determined and compared with that of cleaved HA. The cleavage site is a prominent surface loop adjacent to a novel cavity; cleavage results in structural rearrangements in which the nonpolar amino acids near the new amino terminus bury ionizable residues in the cavity that are implicated in the low-pH-induced conformational change. Amino acid insertions at the cleavage site in HAs of virulent avian viruses and those of viruses isolated from the recent severe outbreak of influenza in humans in Hong Kong would extend this surface loop, facilitating intracellular cleavage.
We have determined the structure of the HA of an avian influenza virus, A/duck/Ukraine/63, a member of the same antigenic subtype, H3, as the virus that caused the 1968 Hong Kong influenza pandemic, ...and a possible progenitor of the pandemic virus. We find that structurally significant differences between the avian and the human HAs are restricted to the receptor-binding site particularly the substitutions Q226L and G228S that cause the site to open and residues within it to rearrange, including the conserved residues Y98, W153, and H183. We have also analyzed complexes formed by the HA with sialopentasaccharides in which the terminal sialic acid is in either α2,3- or α2,6-linkage to galactose. Comparing the structures of complexes in which an α2,3-linked receptor analog is bound to the H3 avian HA or to an H5 avian HA leads to the suggestion that all avian influenza HAs bind to their preferred α2,3-linked receptors similarly, with the analog in a
trans conformation about the glycosidic linkage. We find that α2,6-linked analogs are bound by both human and avian HAs in a
cis conformation, and that the incompatibility of an α2,6-linked receptor with the α2,3-linkage-specific H3 avian HA-binding site is partially resolved by a small change in the position and orientation of the sialic acid. We discuss our results in relation to the mechanism of transfer of influenza viruses between species.
The structure of a stable recombinant ectodomain of influenza hemagglutinin HA2 subunit, EHA2 (23-185), defined by proteolysis studies of the intact bacterial-expressed ectodomain, was determined to ...1.9- angstrom resolution by using x-ray crystallography. The structure reveals a domain composed of N- and C-terminal residues that form an N cap terminating both the N-terminal α -helix and the central coiled coil. The N cap is formed by a conserved sequence, and part of it is found in the neutral pH conformation of HA. The C-terminal 23 residues of the ectodomain form a 72- angstrom long nonhelical structure ordered to within 7 residues of the transmembrane anchor. The structure implies that continuous α helices are not required for membrane fusion at either the N or C termini. The difference in stability between recombinant molecules with and without the N cap sequences suggests that additional free energy for membrane fusion may become available after the formation of the central triple-stranded coiled coil and insertion of the fusion peptide into the target membrane.
Low pH induces a conformational change in the influenza virus haemagglutinin, which then mediates fusion of the viral and host cell membranes. The three-dimensional structure of a fragment of the ...haemagglutinin in this conformation reveals a major refolding of the secondary and tertiary structure of the molecule. The apolar fusion peptide moves at least 100 A to one tip of the molecule. At the other end a helical segment unfolds, a subdomain relocates reversing the chain direction, and part of the structure becomes disordered.
Recognition by a T-cell antigen receptor (TCR) of peptide complexed with a major histocompatibility complex (MHC) molecule occurs through variable loops in the TCR structure which bury almost all the ...available peptide and a much larger area of the MHC molecule. The TCR fits diagonally across the MHC peptide-binding site in a surface feature common to all class I and class II MHC molecules, providing evidence that the nature of binding is general. A broadly applicable binding mode has implications for the mechanism of repertoire selection and the magnitude of alloreactions.
There are 15 subtypes of influenza A virus (H1–H15), all of which are found in avian species. Three caused pandemics in the last century: H1 in 1918 (and 1977), H2 in 1957 and H3 in 1968. In 1997, an ...H5 avian virus and in 1999 an H9 virus caused outbreaks of respiratory disease in Hong Kong. We have determined the three‐dimensional structures of the haemagglutinins (HAs) from H5 avian and H9 swine viruses closely related to the viruses isolated from humans in Hong Kong. We have compared them with known structures of the H3 HA from the virus that caused the 1968 H3 pandemic and of the HA–esterase–fusion (HEF) glycoprotein from an influenza C virus. Structure and sequence comparisons suggest that HA subtypes may have originated by diversification of properties that affected the metastability of HAs required for their membrane fusion activities in viral infection.
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.
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