1i1f
From Proteopedia
(New page: 200px<br /> <applet load="1i1f" size="450" color="white" frame="true" align="right" spinBox="true" caption="1i1f, resolution 2.8Å" /> '''CRYSTAL STRUCTURE OF...) |
|||
| Line 6: | Line 6: | ||
==Overview== | ==Overview== | ||
Designing altered peptide ligands to generate specific immunological, reactivity when bound to class I major histocompatibility complexes is, important for both therapeutic and prophylactic reasons. We have, previously shown that two altered peptides, derived from human, immunodeficiency virus (HIV)-reverse transcriptase (RT) residues 309-317, are more immunogenic in vitro than the wild-type peptide. One peptide, variant, I1Y, was able to stimulate RT-specific cytotoxic T cells from the, blood of three HIV-infected individuals better than the wild-type RT, peptide. Both I1Y and I1F peptide variants increase the cell surface, half-life of the peptide-class I complex approximately 3-fold over that of, the RT peptide but have different immunological activities. These peptides, are candidates for the design of vaccines for HIV due to their increased, immunogenicity. To understand the basis for the increased cell surface, stability compared with wild-type peptide and to understand the, differences in T cell recognition between I1Y and I1F, we determined the, x-ray crystal structures of the two class I MHC-peptide complexes. These, structures indicate that the increased cell surface half-life is due to, pi-pi stacking interactions between Trp-167 of HLA-A2.1 and the aromatic, P1 residues of I1F and I1Y. Comparison of the structures and modeling, potential T cell receptor (TCR) interactions suggests that T cell, interactions and immunogenicity are different between I1Y and I1F for two, reasons. First, subtle changes in the steric and polar properties of the, I1Y peptide affect TCR engagement. Second, water-mediated hydrogen bond, interactions between the P1-Tyr and the P4-Glu peptide residues increase, peptide side chain rigidity of residues critical for TCR engagement. | Designing altered peptide ligands to generate specific immunological, reactivity when bound to class I major histocompatibility complexes is, important for both therapeutic and prophylactic reasons. We have, previously shown that two altered peptides, derived from human, immunodeficiency virus (HIV)-reverse transcriptase (RT) residues 309-317, are more immunogenic in vitro than the wild-type peptide. One peptide, variant, I1Y, was able to stimulate RT-specific cytotoxic T cells from the, blood of three HIV-infected individuals better than the wild-type RT, peptide. Both I1Y and I1F peptide variants increase the cell surface, half-life of the peptide-class I complex approximately 3-fold over that of, the RT peptide but have different immunological activities. These peptides, are candidates for the design of vaccines for HIV due to their increased, immunogenicity. To understand the basis for the increased cell surface, stability compared with wild-type peptide and to understand the, differences in T cell recognition between I1Y and I1F, we determined the, x-ray crystal structures of the two class I MHC-peptide complexes. These, structures indicate that the increased cell surface half-life is due to, pi-pi stacking interactions between Trp-167 of HLA-A2.1 and the aromatic, P1 residues of I1F and I1Y. Comparison of the structures and modeling, potential T cell receptor (TCR) interactions suggests that T cell, interactions and immunogenicity are different between I1Y and I1F for two, reasons. First, subtle changes in the steric and polar properties of the, I1Y peptide affect TCR engagement. Second, water-mediated hydrogen bond, interactions between the P1-Tyr and the P4-Glu peptide residues increase, peptide side chain rigidity of residues critical for TCR engagement. | ||
| + | |||
| + | ==Disease== | ||
| + | Known diseases associated with this structure: Abacavir hypersensitivity, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=142800 142800]], Ankylosing spondylitis, susceptibility to, 1 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=142800 142800]], Hypoproteinemia, hypercatabolic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=109700 109700]], Stevens-Johnson syndrome, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=142800 142800]] | ||
==About this Structure== | ==About this Structure== | ||
| Line 21: | Line 24: | ||
[[Category: human class i mhc]] | [[Category: human class i mhc]] | ||
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 17:25:12 2007'' |
Revision as of 15:18, 12 November 2007
|
CRYSTAL STRUCTURE OF HUMAN CLASS I MHC (HLA-A2.1) COMPLEXED WITH BETA 2-MICROGLOBULIN AND HIV-RT VARIANT PEPTIDE I1Y
Contents |
Overview
Designing altered peptide ligands to generate specific immunological, reactivity when bound to class I major histocompatibility complexes is, important for both therapeutic and prophylactic reasons. We have, previously shown that two altered peptides, derived from human, immunodeficiency virus (HIV)-reverse transcriptase (RT) residues 309-317, are more immunogenic in vitro than the wild-type peptide. One peptide, variant, I1Y, was able to stimulate RT-specific cytotoxic T cells from the, blood of three HIV-infected individuals better than the wild-type RT, peptide. Both I1Y and I1F peptide variants increase the cell surface, half-life of the peptide-class I complex approximately 3-fold over that of, the RT peptide but have different immunological activities. These peptides, are candidates for the design of vaccines for HIV due to their increased, immunogenicity. To understand the basis for the increased cell surface, stability compared with wild-type peptide and to understand the, differences in T cell recognition between I1Y and I1F, we determined the, x-ray crystal structures of the two class I MHC-peptide complexes. These, structures indicate that the increased cell surface half-life is due to, pi-pi stacking interactions between Trp-167 of HLA-A2.1 and the aromatic, P1 residues of I1F and I1Y. Comparison of the structures and modeling, potential T cell receptor (TCR) interactions suggests that T cell, interactions and immunogenicity are different between I1Y and I1F for two, reasons. First, subtle changes in the steric and polar properties of the, I1Y peptide affect TCR engagement. Second, water-mediated hydrogen bond, interactions between the P1-Tyr and the P4-Glu peptide residues increase, peptide side chain rigidity of residues critical for TCR engagement.
Disease
Known diseases associated with this structure: Abacavir hypersensitivity, susceptibility to OMIM:[142800], Ankylosing spondylitis, susceptibility to, 1 OMIM:[142800], Hypoproteinemia, hypercatabolic OMIM:[109700], Stevens-Johnson syndrome, susceptibility to OMIM:[142800]
About this Structure
1I1F is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
Reference
The structural basis for the increased immunogenicity of two HIV-reverse transcriptase peptide variant/class I major histocompatibility complexes., Kirksey TJ, Pogue-Caley RR, Frelinger JA, Collins EJ, J Biol Chem. 1999 Dec 24;274(52):37259-64. PMID:10601290
Page seeded by OCA on Mon Nov 12 17:25:12 2007
