Document Detail


The crystal structure of an octapeptide repeat of the prion protein in complex with a Fab fragment of the POM2 antibody.
MedLine Citation:
PMID:  23629842     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Prion diseases are progressive, infectious neurodegenerative disorders caused primarily by the misfolding of the cellular prion protein (PrP(c)) into an insoluble, protease-resistant, aggregated isoform termed PrP(sc). In native conditions, PrP(c) has a structured C-terminal domain and a highly flexible N-terminal domain. A part of this N-terminal domain consists of 4-5 repeats of an unusual glycine-rich, eight amino acids long peptide known as the octapeptide repeat (OR) domain. In this article, we successfully report the first crystal structure of an OR of PrP(c) bound to the Fab fragment of the POM2 antibody. The structure was solved at a resolution of 2.3 Å by molecular replacement. Although several studies have previously predicted a β-turn-like structure of the unbound ORs, our structure shows an extended conformation of the OR when bound to a molecule of the POM2 Fab indicating that the bound Fab disrupts any putative native β turn conformation of the ORs. Encouraging results from several recent studies have shown that administering small molecule ligands or antibodies targeting the OR domain of PrP result in arresting the progress of peripheral prion infections both in ex vivo and in in vivo models. This makes the structural study of the interactions of POM2 Fab with the OR domain very important as it would help us to design smaller and tighter binding OR ligands.
Authors:
Mridula Swayampakula; Pravas Kumar Baral; Adriano Aguzzi; Nat N V Kav; Michael N G James
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2013-05-31
Journal Detail:
Title:  Protein science : a publication of the Protein Society     Volume:  22     ISSN:  1469-896X     ISO Abbreviation:  Protein Sci.     Publication Date:  2013 Jul 
Date Detail:
Created Date:  2013-06-27     Completed Date:  2014-01-16     Revised Date:  2014-07-01    
Medline Journal Info:
Nlm Unique ID:  9211750     Medline TA:  Protein Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  893-903     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 The Protein Society.
Data Bank Information
Bank Name/Acc. No.:
PDB/4J8R
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MeSH Terms
Descriptor/Qualifier:
Animals
Antibodies, Monoclonal / chemistry*,  metabolism
Binding Sites
Cell Line, Transformed
Crystallography, X-Ray
Hydrophobic and Hydrophilic Interactions
Immunoglobulin Fab Fragments / chemistry*,  metabolism
Mice
Models, Molecular
Oligopeptides / chemistry*,  metabolism
PrPC Proteins / chemistry*,  metabolism
Protein Conformation
Protein Structure, Tertiary
Static Electricity
Grant Support
ID/Acronym/Agency:
P41GM103393/GM/NIGMS NIH HHS; P41RR001209/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Immunoglobulin Fab Fragments; 0/Oligopeptides; 0/PrPC Proteins
Comments/Corrections

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