PDBsum entry 2h6p

Immune system

PDB id: 2h6p

Contents

Protein chains

276 a.a. *

99 a.a. *

Ligands

LYS-PRO-ILE-VAL-VAL-LEU-HIS-GLY-TYR

Waters ×401

* Residue conservation analysis

PDB id:

2h6p

Name:

Immune system

Title:

Crystal structure of hla-b 3501 Presenting the human cytochrome p450 derived peptide, kpivvlhgy

Structure:

Hla-b35. Chain: a. Fragment: extracellular domains alpha 1. Synonym: hla class i histocompatibility antigen, b-35 alpha chain. Engineered: yes. Beta-2-microglobulin. Chain: b. Synonym: beta-2-microglobin. Engineered: yes.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008. Synthetic: yes. Other_details: synthetic construct

Biol. unit:

Trimer (from PQS)

Resolution:

1.90Å R-factor: 0.211 R-free: 0.239

Authors:

J.K.Archbold,W.A.Macdonald,J.Rossjohn

Key ref:

J.K.Archbold et al. (2006). Alloreactivity between disparate cognate and allogeneic pMHC-I complexes is the result of highly focused, peptide-dependent structural mimicry. J Biol Chem, 281, 34324-34332. PubMed id: 16963442 DOI: 10.1074/jbc.M606755200

Date:

31-May-06 Release date: 19-Sep-06

Protein chain

P01889  (1B07_HUMAN) -  HLA class I histocompatibility antigen, B alpha chain from Homo sapiens

Seq: 362 a.a.

Struc: 276 a.a.*

Protein chain

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

Seq: 119 a.a.

Struc: 99 a.a.

* PDB and UniProt seqs differ at 22 residue positions (black crosses)

DOI no: 10.1074/jbc.M606755200

J Biol Chem 281:34324-34332 (2006)

PubMed id: 16963442

Alloreactivity between disparate cognate and allogeneic pMHC-I complexes is the result of highly focused, peptide-dependent structural mimicry.

J.K.Archbold, W.A.Macdonald, J.J.Miles, R.M.Brennan, L.Kjer-Nielsen, J.McCluskey, S.R.Burrows, J.Rossjohn.

ABSTRACT

Our understanding of the molecular mechanisms of T cell alloreactivity remains limited by the lack of systems for which both the T cell receptor allo- and cognate ligand are known. Here we provide evidence that a single alloreactive T cell receptor interacts with analogous structural regions of its cognate ligand, HLA-B*0801(FLRGRAYGL), as its allogeneic ligand, HLA-B*3501(KPIVVLHGY). The crystal structures of the binary peptide-major histocompatibility complexes show marked differences in the conformation of the heavy chains as well as the bound peptides. Nevertheless, both epitopes possess a prominent solvent-exposed aromatic residue at position 7 flanked by a small glycine at position 8 of the peptide determinant. Moreover, regions of close structural homology between the heavy chains of HLA B8 and HLA B35 coincided with regions that have previously been implicated in "hot spots" of T cell receptor recognition. The avidity of this human T cell receptor was also comparable for the allo- and cognate ligand, consistent with the modes of T cell receptor binding being broadly similar for these complexes. Collectively, it appears that highly focused structural mimicry against a diverse structural background provides a basis for the observed alloreactivity in this system. This cross-reactivity underpins the T cell degeneracy inherent in the limited mature T cell repertoire that must respond to a vast diversity of microbial antigens.

Selected figure(s)

Figure 4.
FIGURE 4. Structure of the allogeneic stimulating peptide, KPI, complexed to the MHC. The cytochrome P450 derived peptide, KPIVVLHGY (aqua), sitting in the peptide binding cleft of the MHC, HLA-B^*3501 (green). The surrounding final 2F[o] - F[c] electron density for the peptide is shown in mesh format. This figure shows the positions of key anchor residues (Pro^2 and Tyr^9) and possible TCR contact residues (Val^4, Val^5, and His^7).

Figure 6.
FIGURE 6. Highly focused molecular mimicry between the allo- and cognate ligands explains JL9 cross-reactivity. Surface representation of (self-HLA-B^*0801^FLR (A) and allo-HLA-B^*3501^KPI (B). The surface of HLA-B^*0801^FLR and HLA-B^*3501^KPI differ, especially around the peptides and their binding clefts. The polymorphic residues are colored in orange, the FLRGRAYGL peptide is colored in pink, and the KPIVVLHGY peptide is colored in aqua. For the polymorphic residues, the HLA-B^*0801 residue is listed first followed by the residue number and then the corresponding HLA-B^*3501 residue. The energetic hot spot residues for recognition of HLA-B^*0801^FLR by the LC13 TCR are also shown (yellow). C, overlay of the 1 and 2 helices of HLA-B^*0801 (blue) and HLA-B^*3501 (green). The FLR peptide is colored in pink, and the KPI peptide is colored in aqua. The CDR loops of the LC13 TCR are shown in orange. The MHC residue positions known to be important for LC13 recognition of HLA-B^*0801^FLR are highlighted in yellow. In particular, the three residues of the restriction triad at positions 65, 69, and 155 appear to be conserved structurally.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2006, 281, 34324-34332) copyright 2006.

Figures were selected by the author.