PDBsum entry 2w9e

Immune system

PDB id: 2w9e

Contents

Protein chains

99 a.a. *

215 a.a. *

212 a.a. *

Ligands

SO4

Waters ×42

* Residue conservation analysis

PDB id:

2w9e

Name:

Immune system

Title:

Structure of icsm 18 (anti-prp therapeutic antibody) fab fragment complexed with human prp fragment 119-231

Structure:

Major prion protein. Chain: a. Fragment: residues 119-231. Synonym: prp27-30, prp33-35c, ascr, prp. Engineered: yes. Icsm 18-anti-prp therapeutic fab heavy chain. Chain: h. Icsm 18-anti-prp therapeutic fab light chain. Chain: l

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Mus musculus. Organism_taxid: 10090. Organism_taxid: 10090

Resolution:

2.90Å R-factor: 0.210 R-free: 0.269

Authors:

S.V.Antonyuk,C.R.Trevitt,R.W.Strange,G.S.Jackson,D.Sangar, M.Batchelor,S.Jones,T.Georgiou,S.Cooper,C.Fraser,A.Khalili-Shirazi, A.R.Clarke,S.S.Hasnain,J.Collinge

Key ref:

S.V.Antonyuk et al. (2009). Crystal structure of human prion protein bound to a therapeutic antibody. Proc Natl Acad Sci U S A, 106, 2554-2558. PubMed id: 19204296 DOI: 10.1073/pnas.0809170106

Date:

23-Jan-09 Release date: 03-Feb-09

Protein chain

P04156  (PRIO_HUMAN) -  Major prion protein from Homo sapiens

Seq: 253 a.a.

Struc: 99 a.a.

Protein chain

No UniProt id for this chain

Struc: 215 a.a.

Protein chain

No UniProt id for this chain

Struc: 212 a.a.

DOI no: 10.1073/pnas.0809170106

Proc Natl Acad Sci U S A 106:2554-2558 (2009)

PubMed id: 19204296

Crystal structure of human prion protein bound to a therapeutic antibody.

S.V.Antonyuk, C.R.Trevitt, R.W.Strange, G.S.Jackson, D.Sangar, M.Batchelor, S.Cooper, C.Fraser, S.Jones, T.Georgiou, A.Khalili-Shirazi, A.R.Clarke, S.S.Hasnain, J.Collinge.

ABSTRACT

Prion infection is characterized by the conversion of host cellular prion protein (PrP(C)) into disease-related conformers (PrP(Sc)) and can be arrested in vivo by passive immunization with anti-PrP monoclonal antibodies. Here, we show that the ability of an antibody to cure prion-infected cells correlates with its binding affinity for PrP(C) rather than PrP(Sc). We have visualized this interaction at the molecular level by determining the crystal structure of human PrP bound to the Fab fragment of monoclonal antibody ICSM 18, which has the highest affinity for PrP(C) and the highest therapeutic potency in vitro and in vivo. In this crystal structure, human PrP is observed in its native PrP(C) conformation. Interactions between neighboring PrP molecules in the crystal structure are mediated by close homotypic contacts between residues at position 129 that lead to the formation of a 4-strand intermolecular beta-sheet. The importance of this residue in mediating protein-protein contact could explain the genetic susceptibility and prion strain selection determined by polymorphic residue 129 in human prion disease, one of the strongest common susceptibility polymorphisms known in any human disease.

Selected figure(s)

Figure 2.
The complex between recombinant PrP^119-231 and the ICSM 18-Fab as determined by X-ray crystallography. (A) PrP^119-231 is shown in green with the heavy and light chains of the Fab in cyan and magenta, respectively. (B) Expanded view of the PrP/Fab interface. The participating PrP residues are labeled in black and those from the Fab heavy and light chains in blue and magenta, respectively. Potential hydrogen bonds are shown as dashed lines.

Figure 3.
The interaction of PrP chains in the crystal. (A) Illustration of the intermolecular 4-stranded antiparallel β-sheet formed between neighboring PrP chains (in cyan and green) emphasizing residue 129 at the molecular interface (see Inset). (B) Superimposition of the ovine [red (25)] and human (green) PrP dimers from the respective crystal structures. Note the common occurrence of the 4-stranded intermolecular β-sheet.

Figures were selected by an automated process.