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PDBsum entry 6fft
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Transport protein
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PDB id
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6fft
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PDB id:
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| Name: |
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Transport protein
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Title:
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Neutron structure of human transthyretin (ttr) s52p mutant in complex with tafamidis at room temperature to 2a resolution (quasi-laue)
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Structure:
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Transthyretin. Chain: a, b. Synonym: attr,prealbumin,tbpa. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: ttr, palb. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
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Resolution:
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2.00Å
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R-factor:
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0.161
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R-free:
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0.195
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Authors:
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A.W.Yee,M.Moulin,M.P.Blakeley,M.Haertlein,E.P.Mitchell,V.T.Forsyth
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Key ref:
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A.W.Yee
et al.
(2019).
A molecular mechanism for transthyretin amyloidogenesis.
Nat Commun,
10,
925.
PubMed id:
DOI:
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Date:
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09-Jan-18
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Release date:
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02-Jan-19
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PROCHECK
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Headers
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References
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P02766
(TTHY_HUMAN) -
Transthyretin from Homo sapiens
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Seq:
Struc:
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147 a.a.
116 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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*
PDB and UniProt seqs differ
at 1 residue position (black
cross)
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DOI no:
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Nat Commun
10:925
(2019)
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PubMed id:
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A molecular mechanism for transthyretin amyloidogenesis.
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A.W.Yee,
M.Aldeghi,
M.P.Blakeley,
A.Ostermann,
P.J.Mas,
M.Moulin,
D.de Sanctis,
M.W.Bowler,
C.Mueller-Dieckmann,
E.P.Mitchell,
M.Haertlein,
B.L.de Groot,
E.Boeri Erba,
V.T.Forsyth.
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ABSTRACT
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Human transthyretin (TTR) is implicated in several fatal forms of amyloidosis.
Many mutations of TTR have been identified; most of these are pathogenic, but
some offer protective effects. The molecular basis underlying the vastly
different fibrillation behaviours of these TTR mutants is poorly understood.
Here, on the basis of neutron crystallography, native mass spectrometry and
modelling studies, we propose a mechanism whereby TTR can form amyloid fibrils
via a parallel equilibrium of partially unfolded species that proceeds in favour
of the amyloidogenic forms of TTR. It is suggested that unfolding events within
the TTR monomer originate at the C-D loop of the protein, and that destabilising
mutations in this region enhance the rate of TTR fibrillation. Furthermore, it
is proposed that the binding of small molecule drugs to TTR stabilises
non-amyloidogenic states of TTR in a manner similar to that occurring for the
protective mutants of the protein.
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