The methionine-aromatic motif plays a unique role in stabilizing protein structure.
J Biol Chem
; 287(42): 34979-34991, 2012 Oct 12.
Article
em En
| MEDLINE
| ID: mdl-22859300
ABSTRACT
Of the 20 amino acids, the precise function of methionine (Met) remains among the least well understood. To establish a determining characteristic of methionine that fundamentally differentiates it from purely hydrophobic residues, we have used in vitro cellular experiments, molecular simulations, quantum calculations, and a bioinformatics screen of the Protein Data Bank. We show that approximately one-third of all known protein structures contain an energetically stabilizing Met-aromatic motif and, remarkably, that greater than 10,000 structures contain this motif more than 10 times. Critically, we show that as compared with a purely hydrophobic interaction, the Met-aromatic motif yields an additional stabilization of 1-1.5 kcal/mol. To highlight its importance and to dissect the energetic underpinnings of this motif, we have studied two clinically relevant TNF ligand-receptor complexes, namely TRAIL-DR5 and LTα-TNFR1. In both cases, we show that the motif is necessary for high affinity ligand binding as well as function. Additionally, we highlight previously overlooked instances of the motif in several disease-related Met mutations. Our results strongly suggest that the Met-aromatic motif should be exploited in the rational design of therapeutics targeting a range of proteins.
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1
Base de dados:
MEDLINE
Assunto principal:
Linfotoxina-alfa
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Receptores Tipo I de Fatores de Necrose Tumoral
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Ligante Indutor de Apoptose Relacionado a TNF
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Receptores do Ligante Indutor de Apoptose Relacionado a TNF
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Metionina
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article