Novel quaternary structures of the human prion protein globular domain.

Autor: Bortot LO; Laboratory of Protein Crystallography, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Rangel VL; Laboratory of Protein Crystallography, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Pavlovici FA; Chemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., El Omari K; Diamond Light Source, Harwell Science and Innovation Campus, Didcot, United Kingdom., Wagner A; Diamond Light Source, Harwell Science and Innovation Campus, Didcot, United Kingdom., Brandao-Neto J; Diamond Light Source, Harwell Science and Innovation Campus, Didcot, United Kingdom., Talon R; Diamond Light Source, Harwell Science and Innovation Campus, Didcot, United Kingdom., von Delft F; Diamond Light Source, Harwell Science and Innovation Campus, Didcot, United Kingdom; Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Headington, OX3 7DQ, UK; Department of Biochemistry, University of Johannesburg, Auckland Park, 2006, South Africa., Reidenbach AG; Chemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Vallabh SM; Chemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Minikel EV; Chemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Schreiber S; Chemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA; Department of Chemistry & Chemical Biology, Harvard University, Cambridge, MA, 02138, USA., Nonato MC; Laboratory of Protein Crystallography, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil. Electronic address: cristy@fcfrp.usp.br.
Jazyk: angličtina
Zdroj: Biochimie [Biochimie] 2021 Dec; Vol. 191, pp. 118-125. Date of Electronic Publication: 2021 Sep 10.
DOI: 10.1016/j.biochi.2021.09.005
Abstrakt: Prion disease is caused by the misfolding of the cellular prion protein, PrP C , into a self-templating conformer, PrP Sc . Nuclear magnetic resonance (NMR) and X-ray crystallography revealed the 3D structure of the globular domain of PrP C and the possibility of its dimerization via an interchain disulfide bridge that forms due to domain swap or by non-covalent association of two monomers. On the contrary, PrP Sc is composed by a complex and heterogeneous ensemble of poorly defined conformations and quaternary arrangements that are related to different patterns of neurotoxicity. Targeting PrP C with molecules that stabilize the native conformation of its globular domain emerged as a promising approach to develop anti-prion therapies. One of the advantages of this approach is employing structure-based drug discovery methods to PrP C . Thus, it is essential to expand our structural knowledge about PrP C as much as possible to aid such drug discovery efforts. In this work, we report a crystallographic structure of the globular domain of human PrP C that shows a novel dimeric form and a novel oligomeric arrangement. We use molecular dynamics simulations to explore its structural dynamics and stability and discuss potential implications of these new quaternary structures to the conversion process.
Competing Interests: Declaration of competing interest X All authors have participated in (a) conception and design, or analysis and interpretation of the data; (b) drafting the article or revising it critically for important intellectual content; and (c) approval of the final version. X This manuscript has not been submitted to, nor is under review at, another journal or other publishing venue. X The authors have no affiliation with any organization with a direct or indirect financial interest in the subject matter discussed in the manuscript
(Copyright © 2021 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)
Databáze: MEDLINE
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