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

Anti-viral immunity and the Killer T-cell

T-cell

Antigen Presenting Cell

TcR

MHC-1

CD3CD3

CD8

peptide

Signalling?

T-cell antigen recognition

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

A forest of MHC peptide complexes

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

HLA B*3508-13mer Highly mobile peptide

Varied prominent features

Prominent Landscapes

Super-bulged peptides can display differing degrees of mobility

TcR recognition of the B*3508/13-mer focuseson a bulged region of the peptide

Eat as much as you want?

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

TcR recognition of a super-bulged viral peptide

1-helix

A minimal footprint

Orthogonal dockingLimited MHC contacts

Typical footprintMHC-mediated contacts

CDR2

Alternative docking modes

Rocking atop the rigid epitope

Twice as many peptide-mediated contacts compared to MHC-contacts

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

Conclusions

• Long viral peptides in MHC-I immunity

• Structural basis of recognition of super-bulged viral peptides

• MHC-restriction