5VLN

NMR structure of the N-domain of troponin C bound to switch region of troponin I

5VLN の概要

• エントリーDOI: 10.2210/pdb5vln/pdb
• 関連するPDBエントリー: 5VL6
• NMR情報: BMRB: 30288
• 分子名称: Troponin C, slow skeletal and cardiac muscles,Troponin I, cardiac muscle (1 entity in total)
• 機能のキーワード: cardiac troponin calcium binding protein ef hand, cell invasion, metal binding protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 13495.39

構造登録者

Cai, F.,Hwang, P.M.,Sykes, B.D. (登録日: 2017-04-25, 公開日: 2017-05-24, 最終更新日: 2024-05-15)

主引用文献

Cai, F.,Li, M.X.,Pineda-Sanabria, S.E.,Gelozia, S.,Lindert, S.,West, F.,Sykes, B.D.,Hwang, P.M.
Structures reveal details of small molecule binding to cardiac troponin.
J. Mol. Cell. Cardiol., 101:134-144, 2016

PubMed Abstract: In cardiac and skeletal muscle, the troponin complex turns muscle contraction on and off in a calcium-dependent manner. Many small molecules are known to bind to the troponin complex to modulate its calcium binding affinity, and this may be useful in a broad range of conditions in which striated muscle function is compromised, such as congestive heart failure. As a tool for developing drugs specific for the cardiac isoform of troponin, we have designed a chimeric construct (cChimera) consisting of the regulatory N-terminal domain of cardiac troponin C (cNTnC) fused to the switch region of cardiac troponin I (cTnI), mimicking the key binding event that turns on muscle contraction. We demonstrate by solution NMR spectroscopy that cChimera faithfully reproduces the native interface between cTnI and cNTnC. We determined that small molecules based on diphenylamine can bind to cChimera with a K as low as 10μM. Solution NMR structures show that minimal structural perturbations in cChimera are needed to accommodate 3-methyldiphenylamine (3-mDPA), which is probably why it binds with higher affinity than previously studied compounds like bepridil, despite its significantly smaller size. The unsubstituted aromatic ring of 3-mDPA binds to an inner hydrophobic pocket adjacent to the central beta sheet of cNTnC. However, the methyl-substituted ring is able to bind in two different orientations, either inserting into the cNTnC-cTnI interface or "flipping out" to form contacts primarily with helix C of cNTnC. Our work suggests that preservation of the native interaction between cNTnC and cTnI is key to the development of a high affinity cardiac troponin-specific drug.

PubMed: 27825981
DOI: 10.1016/j.yjmcc.2016.10.016

実験手法

SOLUTION NMR