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2M2P

Structure of [D-HisB24] insulin analogue at pH 8.0

2M2P の概要
エントリーDOI10.2210/pdb2m2p/pdb
関連するPDBエントリー2M2M 2M2N 2M2O
NMR情報BMRB: 18925
分子名称Insulin A chain, Insulin B chain (2 entities in total)
機能のキーワードinsulin, hormone
由来する生物種Homo sapiens (human)
詳細
細胞内の位置Secreted: P01308 P01308
タンパク質・核酸の鎖数2
化学式量合計5808.62
構造登録者
Zakova, L.,Veverka, V.,Jiracek, J. (登録日: 2012-12-29, 公開日: 2013-03-06, 最終更新日: 2024-11-06)
主引用文献Kletvikova, E.,Veverka, V.,Lepsik, M.,Watson, C.J.,Turkenburg, J.P.,Jiracek, J.,Brzozowski, A.M.
Structural integrity of the B24 site in human insulin is important for hormone functionality.
J.Biol.Chem., 288:10230-10240, 2013
Cited by
PubMed Abstract: Despite the recent first structural insight into the insulin-insulin receptor complex, the role of the C terminus of the B-chain of insulin in this assembly remains unresolved. Previous studies have suggested that this part of insulin must rearrange to reveal amino acids crucial for interaction with the receptor. The role of the invariant Phe(B24), one of the key residues of the hormone, in this process remains unclear. For example, the B24 site functionally tolerates substitutions to D-amino acids but not to L-amino acids. Here, we prepared and characterized a series of B24-modified insulin analogues, also determining the structures of [D-HisB24]-insulin and [HisB24]-insulin. The inactive [HisB24]-insulin molecule is remarkably rigid due to a tight accommodation of the L-His side chain in the B24 binding pocket that results in the stronger tethering of B25-B28 residues to the protein core. In contrast, the highly active [D-HisB24]-insulin is more flexible, and the reverse chirality of the B24C(α) atom swayed the D-His(B24) side chain into the solvent. Furthermore, the pocket vacated by Phe(B24) is filled by Phe(B25), which mimics the Phe(B24) side and main chains. The B25→B24 downshift results in a subsequent downshift of Tyr(B26) into the B25 site and the departure of B26-B30 residues away from the insulin core. Our data indicate the importance of the aromatic L-amino acid at the B24 site and the structural invariance/integrity of this position for an effective binding of insulin to its receptor. Moreover, they also suggest limited, B25-B30 only, unfolding of the C terminus of the B-chain upon insulin activation.
PubMed: 23447530
DOI: 10.1074/jbc.M112.448050
主引用文献が同じPDBエントリー
実験手法
SOLUTION NMR
構造検証レポート
Validation report summary of 2m2p
検証レポート(詳細版)ダウンロードをダウンロード

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件を2025-07-16に公開中

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