7UH9

NMR structure of the cNTnC-cTnI chimera bound to W8

7UH9 の概要

• エントリーDOI: 10.2210/pdb7uh9/pdb
• NMR情報: BMRB: 31005
• 分子名称: Troponin C, slow skeletal and cardiac muscles,Troponin I, cardiac muscle, CALCIUM ION, N-(7-aminoheptyl)-5-chloronaphthalene-1-sulfonamide (3 entities in total)
• 機能のキーワード: cardiac troponin, calcium binding protein, ef hand, metal binding protein, calcium modulator
• 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: 14581.10

構造登録者

Cai, F.,Kampourakis, T.,Cockburn, K.T.,Sykes, B.D. (登録日: 2022-03-26, 公開日: 2022-06-15, 最終更新日: 2024-05-15)

主引用文献

Cai, F.,Kampourakis, T.,Cockburn, K.T.,Sykes, B.D.
Drugging the Sarcomere, a Delicate Balance: Position of N-Terminal Charge of the Inhibitor W7.
Acs Chem.Biol., 17:1495-1504, 2022

PubMed Abstract: W7 is a sarcomere inhibitor that decreases the calcium sensitivity of force development in cardiac muscle. W7 binds to the interface of the regulatory domain of cardiac troponin C (cNTnC) and the switch region of troponin I (cTnI), decreasing the binding of cTnI to cNTnC, presumably by electrostatic repulsion between the -NH group of W7 and basic amino acids in cTnI. W7 analogs with a -CO tail are inactive. To evaluate the importance of the location of the charged -NH, we used a series of compounds W4, W6, W8, and W9, which have three less, one less, one more, and two more methylene groups in the tail region than W7. W6, W8, and W9 all bind tighter to cNTnC-cTnI chimera (cChimera) than W7, while W4 binds weaker. W4 and, strikingly, W6 have no effect on calcium sensitivity of force generation, while W8 and W9 decrease calcium sensitivity, but less than W7. The structures of the cChimera-W6 and cChimera-W8 complexes reveal that W6 and W8 bind to the same hydrophobic cleft as W7, with the aliphatic tail taking a similar route to the surface. NMR relaxation data show that internal flexibility in the tail of W7 is very limited. Alignment of the cChimera-W7 structure with the recent cryoEM structures of the cardiac sarcomere in the diastolic and systolic states reveals the critical location of the amino group. Small molecule induced structural changes can therefore affect the tightly balanced equilibrium between tethered components required for rapid contraction.

PubMed: 35649123
DOI: 10.1021/acschembio.2c00126

実験手法

SOLUTION NMR