PDBsum entry 3d3v

Immune system

PDB id: 3d3v

Contents

Protein chains

275 a.a. *

100 a.a. *

200 a.a. *

245 a.a. *

Ligands

LEU-LEU-PHE-GLY-F2F-PRO-VAL-TYR-VAL

GOL ×6

Waters ×27

* Residue conservation analysis

PDB id:

3d3v

Name:

Immune system

Title:

The complex between tcr a6 and human class i mhc hla-a2 with the modified htlv-1 tax (y5(3,4-difluorophenylalanine)) peptide

Structure:

Hla class i histocompatibility antigen, a-2 alpha chain. Chain: a. Synonym: mhc class i antigen a 2. Engineered: yes. Beta-2-microglobulin. Chain: b. Synonym: beta-2-microglobulin form pi 5.3. Engineered: yes. Modified htlv-1 tax (y5(3,4-difluoro)f) peptide.

Source:

Homo sapiens. Organism_taxid: 9606. Gene: hla-a, hlaa. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: b2m, cdabp0092, hdcma22p. Synthetic: yes. Other_details: sequence from viral protein htlv-1 tax. The peptide is commercially available.

Resolution:

2.80Å R-factor: 0.220 R-free: 0.278

Authors:

O.Y.Borbulevych,J.R.Clemens,B.M.Baker

Key ref:

K.H.Piepenbrink et al. (2009). Fluorine substitutions in an antigenic peptide selectively modulate T-cell receptor binding in a minimally perturbing manner. Biochem J, 423, 353-361. PubMed id: 19698083

Date:

12-May-08 Release date: 16-Jun-09

Protein chain

P04439  (1A03_HUMAN) -  HLA class I histocompatibility antigen, A alpha chain from Homo sapiens

Seq: 365 a.a.

Struc: 275 a.a.*

Protein chain

P61769  (B2MG_HUMAN) -  Beta-2-microglobulin from Homo sapiens

Seq: 119 a.a.

Struc: 100 a.a.*

Protein chain

No UniProt id for this chain

Struc: 200 a.a.

Protein chain

P01850  (TRBC1_HUMAN) -  T cell receptor beta constant 1 from Homo sapiens

Seq: 176 a.a.

Struc: 245 a.a.*

* PDB and UniProt seqs differ at 24 residue positions (black crosses)

Biochem J 423:353-361 (2009)

PubMed id: 19698083

Fluorine substitutions in an antigenic peptide selectively modulate T-cell receptor binding in a minimally perturbing manner.

K.H.Piepenbrink, O.Y.Borbulevych, R.F.Sommese, J.Clemens, K.M.Armstrong, C.Desmond, P.Do, B.M.Baker.

ABSTRACT

TCR (T-cell receptor) recognition of antigenic peptides bound and presented by MHC (major histocompatibility complex) molecules forms the basis of the cellular immune response to pathogens and cancer. TCRs bind peptide-MHC complexes weakly and with fast kinetics, features which have hindered detailed biophysical studies of these interactions. Modified peptides resulting in enhanced TCR binding could help overcome these challenges. Furthermore, there is considerable interest in using modified peptides with enhanced TCR binding as the basis for clinical vaccines. In the present study, we examined how fluorine substitutions in an antigenic peptide can selectively impact TCR recognition. Using a structure-guided design approach, we found that fluorination of the Tax peptide [HTLV (human T-cell lymphotropic virus)-1 Tax(11-19)] enhanced binding by the Tax-specific TCR A6, yet weakened binding by the Tax-specific TCR B7. The changes in affinity were consistent with crystallographic structures and fluorine chemistry, and with the A6 TCR independent of other substitutions in the interface. Peptide fluorination thus provides a means to selectively modulate TCR binding affinity without significantly perturbing peptide composition or structure. Lastly, we probed the mechanism of fluorine's effect on TCR binding and we conclude that our results were most consistent with a 'polar hydrophobicity' mechanism, rather than a purely hydrophobic- or electrostatic-based mechanism. This finding should have an impact on other attempts to alter molecular recognition with fluorine.