2W9E

Structure of ICSM 18 (anti-Prp therapeutic antibody) Fab fragment complexed with human Prp fragment 119-231

Summary for 2W9E

• Entry DOI: 10.2210/pdb2w9e/pdb
• Related: 1E1G 1E1J 1E1P 1E1S 1E1U 1E1W 1FKC 1FO7 1H0L 1HJM 1HJN 1I4M 1OEH 1OEI 1QLX 1QLZ 1QM0 1QM1 1QM2 1QM3
• Descriptor: MAJOR PRION PROTEIN, ICSM 18-ANTI-PRP THERAPEUTIC FAB HEAVY CHAIN, ICSM 18-ANTI-PRP THERAPEUTIC FAB LIGHT CHAIN, ... (5 entities in total)
• Functional Keywords: fab, prp, prion, membrane, gpi-anchor, lipoprotein, golgi apparatus, disease mutation, immune system, glycoprotein, cell membrane
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Cell membrane; Lipid-anchor, GPI-anchor. Isoform 2: Cytoplasm: P04156
• Total number of polymer chains: 3
• Total formula weight: 59657.04

Authors

Antonyuk, S.V.,Trevitt, C.R.,Strange, R.W.,Jackson, G.S.,Sangar, D.,Batchelor, M.,Jones, S.,Georgiou, T.,Cooper, S.,Fraser, C.,Khalili-Shirazi, A.,Clarke, A.R.,Hasnain, S.S.,Collinge, J. (deposition date: 2009-01-23, release date: 2009-02-03, Last modification date: 2023-12-13)

Primary citation

Antonyuk, S.V.,Trevitt, C.R.,Strange, R.W.,Jackson, G.S.,Sangar, D.,Batchelor, M.,Cooper, S.,Fraser, C.,Jones, S.,Georgiou, T.,Khalili-Shirazi, A.,Clarke, A.R.,Hasnain, S.S.,Collinge, J.
Crystal Structure of Human Prion Protein Bound to a Therapeutic Antibody.
Proc.Natl.Acad.Sci.USA, 106:2554-, 2009

PubMed 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.

PubMed: 19204296
DOI: 10.1073/PNAS.0809170106

Experimental method

X-RAY DIFFRACTION (2.9 Å)