ArticleThe Journal of biological chemistry2012
The methionine-aromatic motif plays a unique role in stabilizing protein structure.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 174 papers.
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174 citing papers in PubMed.
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- BioGraphX: bridging the sequence-structure gap via physicochemical graph encoding for interpretable subcellular localization prediction.Bioinformatics advances · 2026Article
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- Defining substrate specificities of human RNA capping methyltransferases through quantitative assessment of independent yet cooperative activities.Protein science : a publication of the Protein Society · 2026Article
- Photodynamic Activation of Mammalian and Avian Cholecystokinin Type 1 Receptor Outside of the Pancreatic Acinar Cell Microenvironment.International journal of molecular sciences · 2025Article
- Structure-Guided Virtual Screening of Small Peptide Inhibitors Targeting PD-L1 for Cancer Immunotherapy.ACS medicinal chemistry letters · 2025Article
114 more citing papers are in PubMed but not listed here.
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7 authors.
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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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