The x-ray crystal structure refinements of normal human transthyretin and the amyloidogenic Val-30–&gt;Met variant to 1.7-A resolution.

Hamilton, Jean A.; Steinrauf, L. K.; Braden, Bradford C.; Liepnieks, Juris J.; Benson, Merrill D.; Holmgren, Gösta; Sandgren, Ola; Steen, Lars

doi:10.1016/s0021-9258(18)53792-3

Cited by 190 publications

(49 citation statements)

References 35 publications

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“…The coordinates of the 1.7-A ˚crystal structure of WT TTR (PDB: 1TTA) were obtained from the PDB (45). The 1TTA crystal structure was chosen because it contains coordinates for the full-length protein and did not require modeling of the unstructured N-and C-termini.…”

Section: Model Buildingmentioning

confidence: 99%

Edge Strand Dissociation and Conformational Changes in Transthyretin under Amyloidogenic Conditions

Childers

Daggett

2020

Biophysical Journal

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Section: Model Buildingmentioning

confidence: 99%

Edge Strand Dissociation and Conformational Changes in Transthyretin under Amyloidogenic Conditions

Childers

Daggett

2020

Biophysical Journal

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“…S2, ESI †). In addition, among 5 published TTR structures co-crystalized with T4, 32,[65][66][67] we also observed that the distances between the O atom of -OH groups from T4 and the O atom of the Ser117 sidechain varied greatly from 3.7 to 7.2 Å (Table S3, ESI †).…”

Section: Structural Characteristics Of the Pbde Metabolites Bound To Ttrmentioning

confidence: 79%

Understanding the microscopic binding mechanism of hydroxylated and sulfated polybrominated diphenyl ethers with transthyretin by molecular docking, molecular dynamics simulations and binding free energy calculations

et al. 2017

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Polybrominated diphenyl ethers (PBDEs), one typical type of persistent environmental contaminant, have toxicological effects such as disrupting thyroid homeostasis in the human body. The high binding affinities of hydroxylated metabolites of PBDEs (OH-PBDEs) with transthyretin (TTR) were considered to be one major reason for their extraordinary capacity of passing through the blood-brain barrier via competitive thyroid hormone (T4) transport protein binding. Recent findings showed that sulfated PBDEs can be formed in human liver cytosol as phase-II metabolites. However, experimentally determined data for the TTR binding potential of the sulfated PBDEs are still not available. Therefore, molecular docking and molecular dynamics (MD) simulations were employed in the present study to probe the molecular basis of TTR interacting with hydroxylated and sulfated PBDEs at the atomic level. The docking scores of LeDock were used to construct the structure-based predictive model. The calculated results showed that the sulfated PBDEs have stronger affinity for TTR than the corresponding OH-PBDEs. Further analysis of structural characteristics based on MD simulations indicated that upon the binding of PBDE metabolites, the stability of TTR was enhanced and the dissociation rate of the tetrameric protein structure was potentially decreased. Subsequent binding free energy calculations implied that van der Waals interactions are the dominant forces for the binding of these metabolites of PBDEs at the T4 site of TTR. The residues Ser117/Ser117' and Lys15/Lys15' were identified, by both residue energy decomposition and computational alanine-scanning mutagenesis methods, as key residues which play an important role in determining the binding orientations of the -OSO group of sulfated PBDEs by formation of either hydrogen bonds or electrostatic interactions, respectively. In general, the combination of docking calculations with MD simulations provided a theoretically toxicological assessment for the metabolites of PBDEs, deep insight into the recognition mechanism of TTR for these compounds, and thus more comprehensive understanding of the thyroid-related toxic effects of PBDEs as well.

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“…A estrutura cristalográfica da TTR foi inicialmente descrita por Blake e colaboradores em 1978 (67). Outras estruturas da TTR selvagem (wt) e de variantes mutantes vêm sendo estudadas (66,(68)(69)(70). Estas foram determinadas, em sua grande maioria, no grupo espacial P2 1 2 1 2, sendo a unidade assimétrica composta por um dímero (AB), que carrega uma das faces do sítio de ligação ao T 4 -Figura 1.3B.…”

Section: Transtirretina: Estrutura E Funçãounclassified

“…Desta forma, os valores de IC50 dos ligantes testados com a V30M foram maiores que os apresentados para os mesmos ligantes testados com a TTRwt, com exceção de LUT, API, GC-1 e GC-24 (Tabela 6.1 e Figura 6.3). Isto pode refletir menor afinidade da maioria dos ligantes para a mutante V30M, assim como já observado para o ligante natural T 4 (68,188), e deve estar embasado nas diferenças entre os sítios da mutante e da TTR selvagem, assim como apresentado no capítulo Nos dois sítios dos dois complexos TTR:GEN analisados, o anel fenil de GEN encontra-se voltado para o fundo do canal, em direção à interface de tetramerização.…”

Section: Apottrwt Apov30munclassified

“…Estas são as causas aparentes da modificação da forma do sítio da TTR induzida pela mutação Met30. Estas alterações estruturais podem afetar a interação desta TTR mutante com ligantes, assim como sugerido para a ligação do T 4(68,126). observada em todas as estruturas da apoV30M disponíveis e não foi observada nas estruturas da apoTTRwt, indicando que é decorrência da mutação Met30.Por outro lado, foi reportado que a conformação Ser117u é observada e…”

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Bases moleculares e estruturais do reconhecimento de ligantes pela proteína transtirretina humana

Trivella¹

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incentivo inicial e colaboração fundamental durante o desenvolvimento desta tese. Ao Leonardo Castro Palmieri por sua ajuda e explicações do "mundo da TTR". Ao Lucas Bleicher pelos ensinamentos em cristalografia e companheirismo nas coletas de dados no LNLS. Ao Prof. Carlos A. Montanari e ao Helton J. Wiggers pelos ensinamentos em calorimetria. Ao Prof. Ronaldo Nagem, Prof. Ricardo Aparicio e Prof. Eduardo Horjales pela ajuda em cristalografia.Aos professores: Antonio José da Costa Filho (Jabá), Richard Garratt e Glaucius Oliva, pelas excelentes disciplinas ministradas. À Ana Carolina Figueira pela "consultoria científica" e amizade.À Maria Auxiliadora Morim Santos, que faz jus a seu nome, sempre nos ajudando nas tarefas de laboratório e burocráticas.Aos técnicos Kelven Ulisses, Su, Bianca, Bel e Andressa.Ao João Renato, Humberto, Wanius e Caqui pela amizade e ensinamentos durante estes anos. À Fernanda Batista pelas trocas de informação e companheirismo na sala 08.Ao Caio e ao Flávio meus queridos ex-alunos de IC.Ao Leo e ao Bachega pelas discussões em química.

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The x-ray crystal structure refinements of normal human transthyretin and the amyloidogenic Val-30–>Met variant to 1.7-A resolution.

Cited by 190 publications

References 35 publications

Edge Strand Dissociation and Conformational Changes in Transthyretin under Amyloidogenic Conditions

Edge Strand Dissociation and Conformational Changes in Transthyretin under Amyloidogenic Conditions

Understanding the microscopic binding mechanism of hydroxylated and sulfated polybrominated diphenyl ethers with transthyretin by molecular docking, molecular dynamics simulations and binding free energy calculations

Bases moleculares e estruturais do reconhecimento de ligantes pela proteína transtirretina humana

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