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DOI | 10.2210/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: 23350654DOI: 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) |
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