Phosphorylation and dephosphorylation of proteins by kinases and phosphatases are central to cellular responses and function. The structural effects of serine and threonine phosphorylation were examined in peptides and in proteins, by circular dichroism, NMR spectroscopy, bioinformatics analysis of the PDB, small-molecule X-ray crystallography, and computational investigations. Phosphorylation of both serine and threonine residues induces substantial conformational restriction in their physiologically more important dianionic forms. Threonine exhibits a particularly strong disorder-to-order transition upon phosphorylation, with dianionic phosphothreonine preferentially adopting a cyclic conformation with restricted φ (φ ~ –60 ̊) stabilized by three noncovalent interactions: a strong intraresidue phosphate-amide hydrogen bond, an n→π* interaction between consecutive carbonyls, and an n→σ* interaction
between the phosphate Oγ lone pair and the antibonding orbital of C–Hβ that restricts the χ2 side chain conformation. Proline is unique among the canonical amino acids for its covalent cyclization on the backbone. Phosphothreonine can mimic proline's backbone cyclization via noncovalent interactions. The preferred torsions of dianionic phosphothreonine are φ,ψ = polyproline II helix > α-helix (φ ~ –60 ̊); χ1 = g–; χ2 ~ +115 ̊ (eclipsed C–H/O–P bonds). This structural signature is observed in diverse proteins, including in the activation loops of protein kinases and in protein-protein interactions. In total, these results suggest a structural basis for the differential use and evolution of threonine versus serine phosphorylation sites in proteins, with serine phosphorylation typically inducing smaller, rheostat-like changes, versus threonine phosphorylation promoting larger, step function-like switches, in proteins.
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Noncovalent Bonds through Sigma and Pi-Hole Located on the Same Molecule. Guiding Principles and Comparisons
Over the last years, scientific interest in noncovalent interactions based on the presence of electron-depleted regions called σ-holes or π-holes has markedly accelerated. Their high directionality and strength, comparable to hydrogen bonds, has been documented in many fields of modern chemistry. The current review gathers and digests recent results concerning these bonds, with a focus on those systems where both σ and π-holes are present on the same molecule. The underlying principles guiding the bonding in both sorts of interactions are discussed, and the trends that emerge from recent work offer a guide as to how one might design systems that allow multiple noncovalent bonds to occur simultaneously, or that prefer one bond type over another.
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- Award ID(s):
- 1954310
- NSF-PAR ID:
- 10226290
- Date Published:
- Journal Name:
- Molecules
- Volume:
- 26
- Issue:
- 6
- ISSN:
- 1420-3049
- Page Range / eLocation ID:
- 1740
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.3390/molecules26061740
