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4FI7

Kinetic Stabilization of transthyretin through covalent modification of K15 by 3-(5-(3,5-dichloro-4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)-benzenesulfonamide

4FI7 の概要
エントリーDOI10.2210/pdb4fi7/pdb
関連するPDBエントリー3HJ0 4FI6 4FI8
分子名称Transthyretin, 3-[5-(3,5-dichloro-4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl]benzenesulfonyl fluoride (3 entities in total)
機能のキーワードhormone, binding protein, covalent kinetic stabilizer, hormone-hormone inhibitor complex, hormone/hormone inhibitor
由来する生物種Homo sapiens (human)
細胞内の位置Secreted: P02766
タンパク質・核酸の鎖数2
化学式量合計28333.09
構造登録者
Connelly, S.,Grimster, N.,Wilson, I.A.,Kelly, J.W. (登録日: 2012-06-08, 公開日: 2013-02-20, 最終更新日: 2024-11-20)
主引用文献Grimster, N.P.,Connelly, S.,Baranczak, A.,Dong, J.,Krasnova, L.B.,Sharpless, K.B.,Powers, E.T.,Wilson, I.A.,Kelly, J.W.
Aromatic Sulfonyl Fluorides Covalently Kinetically Stabilize Transthyretin to Prevent Amyloidogenesis while Affording a Fluorescent Conjugate.
J.Am.Chem.Soc., 135:5656-5668, 2013
Cited by
PubMed Abstract: Molecules that bind selectively to a given protein and then undergo a rapid chemoselective reaction to form a covalent conjugate have utility in drug development. Herein a library of 1,3,4-oxadiazoles substituted at the 2 position with an aryl sulfonyl fluoride and at the 5 position with a substituted aryl known to have high affinity for the inner thyroxine binding subsite of transthyretin (TTR) was conceived of by structure-based design principles and was chemically synthesized. When bound in the thyroxine binding site, most of the aryl sulfonyl fluorides react rapidly and chemoselectively with the pKa-perturbed K15 residue, kinetically stabilizing TTR and thus preventing amyloid fibril formation, known to cause polyneuropathy. Conjugation t50s range from 1 to 4 min, ~1400 times faster than the hydrolysis reaction outside the thyroxine binding site. X-ray crystallography confirms the anticipated binding orientation and sheds light on the sulfonyl fluoride activation leading to the sulfonamide linkage to TTR. A few of the aryl sulfonyl fluorides efficiently form conjugates with TTR in plasma. Eleven of the TTR covalent kinetic stabilizers synthesized exhibit fluorescence upon conjugation and therefore could have imaging applications as a consequence of the environment sensitive fluorescence of the chromophore.
PubMed: 23350654
DOI: 10.1021/ja311729d
主引用文献が同じPDBエントリー
実験手法
X-RAY DIFFRACTION (1.402 Å)
構造検証レポート
Validation report summary of 4fi7
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2024-11-20に公開中

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