6NZN

Dimer-of-dimer amyloid fibril structure of glucagon

6NZN の概要

• エントリーDOI: 10.2210/pdb6nzn/pdb
• NMR情報: BMRB: 30572
• 分子名称: Glucagon (1 entity in total)
• 機能のキーワード: amyloid, hormone, protein fibril
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 16
• 化学式量合計: 55788.50

構造登録者

Gelenter, M.D.,Smith, K.J.,Liao, S.Y.,Mandala, V.S.,Dregni, A.J.,Lamm, M.S.,Tian, Y.,Wei, X.,Pochan, D.J.,Tucker, T.J.,Su, Y.,Hong, M. (登録日: 2019-02-14, 公開日: 2019-06-05, 最終更新日: 2024-05-15)

主引用文献

Gelenter, M.D.,Smith, K.J.,Liao, S.Y.,Mandala, V.S.,Dregni, A.J.,Lamm, M.S.,Tian, Y.,Xu, W.,Pochan, D.J.,Tucker, T.J.,Su, Y.,Hong, M.
The peptide hormone glucagon forms amyloid fibrils with two coexisting beta-strand conformations.
Nat.Struct.Mol.Biol., 26:592-598, 2019

PubMed Abstract: Glucagon and insulin maintain blood glucose homeostasis and are used to treat hypoglycemia and hyperglycemia, respectively, in patients with diabetes. Whereas insulin is stable for weeks in its solution formulation, glucagon fibrillizes rapidly at the acidic pH required for solubility and is therefore formulated as a lyophilized powder that is reconstituted in an acidic solution immediately before use. Here we use solid-state NMR to determine the atomic-resolution structure of fibrils of synthetic human glucagon grown at pharmaceutically relevant low pH. Unexpectedly, two sets of chemical shifts are observed, indicating the coexistence of two β-strand conformations. The two conformations have distinct water accessibilities and intermolecular contacts, indicating that they alternate and hydrogen bond in an antiparallel fashion along the fibril axis. Two antiparallel β-sheets assemble with symmetric homodimer cross sections. This amyloid structure is stabilized by numerous aromatic, cation-π, polar and hydrophobic interactions, suggesting mutagenesis approaches to inhibit fibrillization could improve this important drug.

PubMed: 31235909
DOI: 10.1038/s41594-019-0238-6

実験手法

SOLID-STATE NMR