 |
PDBsum entry 6gnm
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Transport protein
|
PDB id
|
|
|
|
6gnm
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Interspecies variation between fish and human transthyretins in their binding of thyroid-Disrupting chemicals.
|
|
|
Authors
|
|
J.Zhang,
C.Grundström,
K.Brännström,
I.Iakovleva,
M.Lindberg,
A.Olofsson,
P.L.Andersson,
A.E.Sauer-Eriksson.
|
|
|
Ref.
|
|
Environ Sci Technol, 2018,
52,
11865-11874.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Thyroid-disrupting chemicals (TDCs) are xenobiotics that can interfere with the
endocrine system and cause adverse effects in organisms and their offspring.
TDCs affect both the thyroid gland and regulatory enzymes associated with
thyroid hormone homeostasis. Transthyretin (TTR) is found in the serum and
cerebrospinal fluid of vertebrates, where it transports thyroid hormones. Here,
we explored the interspecies variation in TDC binding to human and fish TTR
(exemplified by Gilthead seabream ( Sparus aurata)). The in vitro binding
experiments showed that TDCs bind with equal or weaker affinity to seabream TTR
than to the human TTR, in particular, the polar TDCs (>500-fold lower
affinity). Crystal structures of the seabream TTR-TDC complexes revealed that
all TDCs bound at the thyroid binding sites. However, amino acid substitution of
Ser117 in human TTR to Thr117 in seabream prevented polar TDCs from binding deep
in the hormone binding cavity, which explains their low affinity to seabream
TTR. Molecular dynamics and in silico alanine scanning simulation also suggested
that the protein backbone of seabream TTR is more rigid than the human one and
that Thr117 provides fewer electrostatic contributions than Ser117 to ligand
binding. This provides an explanation for the weaker affinities of the ligands
that rely on electrostatic interactions with Thr117. The lower affinities of
TDCs to fish TTR, in particular the polar ones, could potentially lead to milder
thyroid-related effects in fish.
|
|
|
Secondary reference #1
|
|
|
Title
|
|
Structure-Based virtual screening protocol for in silico identification of potential thyroid disrupting chemicals targeting transthyretin.
|
|
|
Authors
|
|
J.Zhang,
A.Begum,
K.Brännström,
C.Grundström,
I.Iakovleva,
A.Olofsson,
A.E.Sauer-Eriksson,
P.L.Andersson.
|
|
|
Ref.
|
|
Environ Sci Technol, 2016,
50,
11984-11993.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
|
|
|
|
