PMID- 25471691
OWN - NLM
STAT- MEDLINE
DCOM- 20150413
LR  - 20181113
IS  - 1521-4141 (Electronic)
IS  - 0014-2980 (Print)
IS  - 0014-2980 (Linking)
VI  - 45
IP  - 2
DP  - 2015 Feb
TI  - Structural basis for ineffective T-cell responses to MHC anchor residue-improved 
      "heteroclitic" peptides.
PG  - 584-91
LID - 10.1002/eji.201445114 [doi]
AB  - MHC anchor residue-modified "heteroclitic" peptides have been used in many cancer 
      vaccine trials and often induce greater immune responses than the wild-type 
      peptide. The best-studied system to date is the decamer MART-1/Melan-A26-35 
      peptide, EAAGIGILTV, where the natural alanine at position 2 has been modified to 
      leucine to improve human leukocyte antigen (HLA)-A*0201 anchoring. The resulting 
      ELAGIGILTV peptide has been used in many studies. We recently showed that T cells 
      primed with the ELAGIGILTV peptide can fail to recognize the natural 
      tumor-expressed peptide efficiently, thereby providing a potential molecular 
      reason for why clinical trials of this peptide have been unsuccessful. Here, we 
      solved the structure of a TCR in complex with HLA-A*0201-EAAGIGILTV peptide and 
      compared it with its heteroclitic counterpart , HLA-A*0201-ELAGIGILTV. The data 
      demonstrate that a suboptimal anchor residue at position 2 enables the TCR to 
      "pull" the peptide away from the MHC binding groove, facilitating extra contacts 
      with both the peptide and MHC surface. These data explain how a TCR can 
      distinguish between two epitopes that differ by only a single MHC anchor residue 
      and demonstrate how weak MHC anchoring can enable an induced-fit interaction with 
      the TCR. Our findings constitute a novel demonstration of the extreme sensitivity 
      of the TCR to minor alterations in peptide conformation.
CI  - (c) 2014 The Authors. European Journal of Immunology Published by Wiley-VCH Verlag 
      GmbH & Co. KGaA, Weinheim.
FAU - Madura, Florian
AU  - Madura F
AD  - Division of Infection and Immunity, Cardiff University School of Medicine, Heath 
      Park, Cardiff, UK.
FAU - Rizkallah, Pierre J
AU  - Rizkallah PJ
FAU - Holland, Christopher J
AU  - Holland CJ
FAU - Fuller, Anna
AU  - Fuller A
FAU - Bulek, Anna
AU  - Bulek A
FAU - Godkin, Andrew J
AU  - Godkin AJ
FAU - Schauenburg, Andrea J
AU  - Schauenburg AJ
FAU - Cole, David K
AU  - Cole DK
FAU - Sewell, Andrew K
AU  - Sewell AK
LA  - eng
GR  - 100327/Wellcome Trust/United Kingdom
GR  - BB/H001085/1/Biotechnology and Biological Sciences Research Council/United 
      Kingdom
GR  - WT095767/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20141228
PL  - Germany
TA  - Eur J Immunol
JT  - European journal of immunology
JID - 1273201
RN  - 0 (Epitopes, T-Lymphocyte)
RN  - 0 (HLA-A*02:01 antigen)
RN  - 0 (HLA-A2 Antigen)
RN  - 0 (MART-1 Antigen)
RN  - 0 (Peptides)
RN  - 0 (Receptors, Antigen, T-Cell, alpha-beta)
RN  - 0 (Recombinant Proteins)
RN  - GMW67QNF9C (Leucine)
RN  - OF5P57N2ZX (Alanine)
SB  - IM
CIN - Eur J Immunol. 2015 Feb;45(2):380-2. PMID: 25581444
MH  - Alanine/*chemistry/genetics
MH  - Amino Acid Sequence
MH  - Amino Acid Substitution
MH  - Crystallography, X-Ray
MH  - Epitopes, T-Lymphocyte/genetics/immunology/*metabolism
MH  - Escherichia coli/genetics/metabolism
MH  - Gene Expression
MH  - HLA-A2 Antigen/*chemistry/genetics/immunology
MH  - Humans
MH  - Leucine/*chemistry/genetics
MH  - MART-1 Antigen/*chemistry/genetics/immunology
MH  - Models, Molecular
MH  - Molecular Sequence Data
MH  - Peptides/*chemistry/genetics/immunology
MH  - Protein Binding
MH  - Protein Interaction Domains and Motifs
MH  - Receptors, Antigen, T-Cell, alpha-beta/*chemistry/genetics/immunology
MH  - Recombinant Proteins/chemistry/genetics/immunology
MH  - T-Lymphocytes, Cytotoxic/cytology/immunology/metabolism
PMC - PMC4357396
OTO - NOTNLM
OT  - Cross-reactivity
OT  - Crystal structure
OT  - MART-1
OT  - Melan-A
OT  - Melanoma
OT  - Peptide-major histocompatibility complex
OT  - Surface plasmon resonance
OT  - T-cell
OT  - TCR
EDAT- 2014/12/05 06:00
MHDA- 2015/04/14 06:00
PMCR- 2015/03/12
CRDT- 2014/12/05 06:00
PHST- 2014/08/09 00:00 [received]
PHST- 2014/10/03 00:00 [revised]
PHST- 2014/11/26 00:00 [accepted]
PHST- 2014/12/05 06:00 [entrez]
PHST- 2014/12/05 06:00 [pubmed]
PHST- 2015/04/14 06:00 [medline]
PHST- 2015/03/12 00:00 [pmc-release]
AID - 10.1002/eji.201445114 [doi]
PST - ppublish
SO  - Eur J Immunol. 2015 Feb;45(2):584-91. doi: 10.1002/eji.201445114. Epub 2014 Dec 
      28.