Structural evidence for asymmetric ligand binding to transthyretin

doi:10.1107/S1399004715010585

	Structural evidence for asymmetric ligand binding to transthyretin
	Cianci, Michele 1; Folli, Claudia 2; Zonta, Francesco3 ; Florio, Paola 4; Berni, Rodolfo 4; Zanotti, Giuseppe 5
	2015-08
发表期刊	ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY (IF:2.6[JCR-2023],5.2[5-Year])
ISSN	2059-7983
卷号	71 页码:1582-1592
发表状态	已发表
DOI	10.1107/S1399004715010585
摘要	Human transthyretin (TTR) represents a notable example of an amyloidogenic protein, and several compounds that are able to stabilize its native state have been proposed as effective drugs in the therapy of TTR amyloidosis. The two thyroxine (T4) binding sites present in the TTR tetramer display negative binding cooperativity. Here, structures of TTR in complex with three natural polyphenols (pterostilbene, quercetin and apigenin) have been determined, in which this asymmetry manifests itself as the presence of a main binding site with clear ligand occupancy and related electron density and a second minor site with a much lower ligand occupancy. The results of an analysis of the structural differences between the two binding sites are consistent with such a binding asymmetry. The different ability of TTR ligands to saturate the two T4 binding sites of the tetrameric protein can be ascribed to the different affinity of ligands for the weaker binding site. In comparison, the high-affinity ligand tafamidis, co-crystallized under the same experimental conditions, was able to fully saturate the two T4 binding sites. This asymmetry is characterized by the presence of small but significant differences in the conformation of the cavity of the two binding sites. Molecular-dynamics simulations suggest the presence of even larger differences in solution. Competition binding assays carried out in solution revealed the presence of a preferential binding site in TTR for the polyphenols pterostilbene and quercetin that was different from the preferential binding site for T4. The TTR binding asymmetry could possibly be exploited for the therapy of TTR amyloidosis by using a cocktail of two drugs, each of which exhibits preferential binding for a distinct binding site, thus favouring saturation of the tetrameric protein and consequently its stabilization.
关键词	transthyretin amyloidosis protein misfolding negative cooperativity fibrillogenesis inhibitors transthyretin stabilizers
收录类别	SCI
语种	英语
资助项目	European Community[283570]
WOS研究方向	Biochemistry & Molecular Biology ; Biophysics ; Crystallography
WOS类目	Biochemical Research Methods ; Biochemistry & Molecular Biology ; Biophysics ; Crystallography
WOS记录号	WOS:000359354800001
出版者	INT UNION CRYSTALLOGRAPHY
WOS关键词	HUMAN-SERUM PREALBUMIN ; NATIVE-STATE ; NEGATIVE COOPERATIVITY ; ANGSTROM RESOLUTION ; DATA QUALITY ; PROTEIN ; POTENT ; AMYLOIDOSIS ; INHIBITORS ; AMYLOIDOGENESIS
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/2165
专题	免疫化学研究所_特聘教授组_功能筛选实验室免疫化学研究所_特聘教授组_Michael Levitt组
通讯作者	Berni, Rodolfo
作者单位	1.DESY, EMBL Hamburg Outstn, D-22603 Hamburg, Germany 2.Univ Parma, Dept Food Sci, I-43124 Parma, Italy 3.ShanghaiTech Univ, Shangai Inst Adv Immunochem Studies, Shanghai 201210, Peoples R China 4.Univ Parma, Dept Life Sci, I-43124 Parma, Italy 5.Univ Padua, Dept Biomed Sci, I-35131 Padua, Italy
推荐引用方式 GB/T 7714	Cianci, Michele,Folli, Claudia,Zonta, Francesco,et al. Structural evidence for asymmetric ligand binding to transthyretin[J]. ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY,2015,71:1582-1592.
APA	Cianci, Michele,Folli, Claudia,Zonta, Francesco,Florio, Paola,Berni, Rodolfo,&Zanotti, Giuseppe.(2015).Structural evidence for asymmetric ligand binding to transthyretin.ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY,71,1582-1592.
MLA	Cianci, Michele,et al."Structural evidence for asymmetric ligand binding to transthyretin".ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY 71(2015):1582-1592.