The Structure and Function of Large Molecular Assemblies 38 th Crystallographic meeting, Erice
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Transcript of The Structure and Function of Large Molecular Assemblies 38 th Crystallographic meeting, Erice
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The Structure and Function of Large Molecular Assemblies
38th Crystallographic meeting, Erice
June 2006
TcR recognition of super-bulged viral epitopes
Jamie Rossjohn
The Dept. of Biochemistry & Molecular Biology
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Anti-viral immunity and the Killer T-cell
T-cell
Antigen Presenting Cell
TcR
MHC-1
CD3CD3
CD8
peptide
Signalling?
T-cell antigen recognition
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classical MHC-class I
MHC genes are highly polymorphic
4
7MHC anchor residues
Potential TcR contact points
MHC
TcRPolymorphisms are concentrated in the cleftAlleles differ by single residues or up to 30 residues
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A forest of MHC peptide complexes
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CTL response
B*3501
binding CTL response
binding
13-mer
9-mer
11-mer
CTL response and HLA-binding properties
B*3508
B*3501 156 Leu B*3508 156 Arg
- ++
+++ ++
+ +
++++++
+
+
+
-
13-mer LPEPLPQGQLTAYB35 motif * P** * * * * * * ** Y
P2 P
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HLA B*3508-13mer Highly mobile peptide
Varied prominent features
Prominent Landscapes
Super-bulged peptides can display differing degrees of mobility
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TcR recognition of the B*3508/13-mer focuseson a bulged region of the peptide
Eat as much as you want?
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TcR recognition of a super-bulged peptide
Do such epitopes act as an obstacle for TCR ligation?
Does the TcR deform the peptide upon ligation?
Hypothesis: This structural investigation will provide insights into MHC-restriction
Aim: Establish the structural basis of TcR recognition of super-bulged epitopes
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TcR recognition of a super-bulged viral peptide
1-helix
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A minimal footprint
Orthogonal dockingLimited MHC contacts
Typical footprintMHC-mediated contacts
CDR2
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Alternative docking modes
Rocking atop the rigid epitope
Twice as many peptide-mediated contacts compared to MHC-contacts
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A restricted response, yet alloreactive
Restriction triad
Cannot “see” B*3501Cross-reacts onto B*4402
B*3508
B*3501
B*3508 Kd = 9.9 M B*3501 Kd = 35.1 M
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Conclusions
• Long viral peptides in MHC-I immunity
• Structural basis of recognition of super-bulged viral peptides
• MHC-restriction
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