PDBsum entry 3fqw

Immune system

PDB id: 3fqw

Contents

Protein chains

275 a.a. *

98 a.a. *

Ligands

ARG-VAL-ALA-SER-PRO-THR-SER-GLY-VAL

Metals

_CD ×5

_CO

Waters ×337

* Residue conservation analysis

PDB id:

3fqw

Name:

Immune system

Title:

Phosphorylation of self-peptides alters human leukocyte antigen class i-restricted antigen presentation and generates tumor specific epitopes

Structure:

Hla class i histocompatibility antigen, a-2 alpha chain. Chain: a. Fragment: extracellular domains alpha1, alpha2, alpha3, unp residues 25-299. Synonym: mhc class i antigen a 2. Engineered: yes. Beta-2-microglobulin. Chain: b. Engineered: yes.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: hla-a, hlaa. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: b2m. Synthetic: yes. Other_details: synthetic peptide

Resolution:

1.93Å R-factor: 0.170 R-free: 0.196

Authors:

J.Petersen,J.Rossjohn

Key ref:

J.Petersen et al. (2009). Phosphorylated self-peptides alter human leukocyte antigen class I-restricted antigen presentation and generate tumor-specific epitopes. Proc Natl Acad Sci U S A, 106, 2776-2781. PubMed id: 19196958 DOI: 10.1073/pnas.0812901106

Date:

07-Jan-09 Release date: 03-Mar-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: 98 a.a.

* PDB and UniProt seqs differ at 19 residue positions (black crosses)

DOI no: 10.1073/pnas.0812901106

Proc Natl Acad Sci U S A 106:2776-2781 (2009)

PubMed id: 19196958

Phosphorylated self-peptides alter human leukocyte antigen class I-restricted antigen presentation and generate tumor-specific epitopes.

J.Petersen, S.J.Wurzbacher, N.A.Williamson, S.H.Ramarathinam, H.H.Reid, A.K.Nair, A.Y.Zhao, R.Nastovska, G.Rudge, J.Rossjohn, A.W.Purcell.

ABSTRACT

Human leukocyte antigen (HLA) class I molecules present a variety of posttranslationally modified epitopes at the cell surface, although the consequences of such presentation remain largely unclear. Phosphorylation plays a critical cellular role, and deregulation in phosphate metabolism is associated with disease, including autoimmunity and tumor immunity. We have solved the high-resolution structures of 3 HLA A2-restricted phosphopeptides associated with tumor immunity and compared them with the structures of their nonphosphorylated counterparts. Phosphorylation of the epitope was observed to affect the structure and mobility of the bound epitope. In addition, the phosphoamino acid stabilized the HLA peptide complex in an epitope-specific manner and was observed to exhibit discrete flexibility within the antigen-binding cleft. Collectively, our data suggest that phosphorylation generates neoepitopes that represent demanding targets for T-cell receptor ligation. These findings provide insights into the mode of phosphopeptide presentation by HLA as well as providing a platform for the rational design of a generation of posttranslationally modified tumor vaccines.

Selected figure(s)

Figure 1.
Peptide conformations within the antigen-binding cleft. CDC25b (A), IRS2 (B), β-catenin (C), CDC25b-phospho (D), IRS2-phospho (E), and β-catenin–phospho (F). Blue mesh indicates unbiased 2Fo-Fc maps contoured at 1σ. Yellow indicates nonphosphorylated peptides. Green indicates phosphorylated peptides. The bound peptide is shown from a side-on view with the α2-helix removed for clarity.

Figure 2.
Interactions of the phosphorylation site in nonphosphopeptide and phosphopeptide HLA A2 complexes. Accommodation of the phosphate moiety by HLA A2 is accompanied by changed interactions in the complex, adding to the differential presentation of altered self. Stick representation of peptides and of heavy-chain side chains that interact with the phosphorylation site. Yellow indicates nonphospho-pHLA A2 complexes. Green indicates phospho-pHLA A2 complexes. (A–C) Phosphorylation of P5-Ser in CDC25b leads to an altered peptide conformation attributable to steric constraints. (D–F) Phosphorylation of P4-Ser in IRS2 gives rise to numerous interactions and subtly alters the conformation of Arg 65 and Lys 66. (G–I) Phosphorylation of P4-Ser in β-catenin stabilizes the mobile peptide residues P3 to P6.

Figures were selected by an automated process.