6YAA

Structure of the (SR) Ca2+-ATPase bound to the inhibitor compound CAD204520 and TNP-ATP

6YAA の概要

• エントリーDOI: 10.2210/pdb6yaa/pdb
• 分子名称: Sarcoplasmic/endoplasmic reticulum calcium ATPase 1, SPIRO(2,4,6-TRINITROBENZENE[1,2A]-2O',3O'-METHYLENE-ADENINE-TRIPHOSPHATE, 4-[2-[(2~{R})-2-[3-propyl-6-(trifluoromethyloxy)-1~{H}-indol-2-yl]piperidin-1-yl]ethyl]morpholine, ... (4 entities in total)
• 機能のキーワード: p-type atpase, inhibitory complex, calcium-transporting atpase, hydrolase
• 由来する生物種: Oryctolagus cuniculus (Rabbit)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 110799.46

構造登録者

Heit, S.,Marchesini, M.,Gherli, A.,Montanaro, A.,Patrizi, L.,Sorrentino, C.,Pagliaro, L.,Rompietti, C.,Kitara, S.,Olesen, C.E.,Moller, J.V.,Savi, M.,Bocchi, L.,Vilella, R.,Rizzi, F.,Baglione, M.,Rastelli, G.,Loiacona, C.,La Starza, R.,Mecucci, C.,Stegmair, K.,Aversa, F.,Stilli, D.,Lund Winther, A.M.,Sportoletti, P.,Dalby-Brown, W.,Roti, G.,Bublitz, M. (登録日: 2020-03-11, 公開日: 2020-05-20, 最終更新日: 2024-10-23)

主引用文献

Marchesini, M.,Gherli, A.,Montanaro, A.,Patrizi, L.,Sorrentino, C.,Pagliaro, L.,Rompietti, C.,Kitara, S.,Heit, S.,Olesen, C.E.,Moller, J.V.,Savi, M.,Bocchi, L.,Vilella, R.,Rizzi, F.,Baglione, M.,Rastelli, G.,Loiacono, C.,La Starza, R.,Mecucci, C.,Stegmaier, K.,Aversa, F.,Stilli, D.,Lund Winther, A.M.,Sportoletti, P.,Bublitz, M.,Dalby-Brown, W.,Roti, G.
Blockade of Oncogenic NOTCH1 with the SERCA Inhibitor CAD204520 in T Cell Acute Lymphoblastic Leukemia.
Cell Chem Biol, 27:678-, 2020

PubMed Abstract: The identification of SERCA (sarco/endoplasmic reticulum calcium ATPase) as a target for modulating gain-of-function NOTCH1 mutations in Notch-dependent cancers has spurred the development of this compound class for cancer therapeutics. Despite the innate toxicity challenge associated with SERCA inhibition, we identified CAD204520, a small molecule with better drug-like properties and reduced off-target Ca toxicity compared with the SERCA inhibitor thapsigargin. In this work, we describe the properties and complex structure of CAD204520 and show that CAD204520 preferentially targets mutated over wild-type NOTCH1 proteins in T cell acute lymphoblastic leukemia (T-ALL) and mantle cell lymphoma (MCL). Uniquely among SERCA inhibitors, CAD204520 suppresses NOTCH1-mutated leukemic cells in a T-ALL xenografted model without causing cardiac toxicity. This study supports the development of SERCA inhibitors for Notch-dependent cancers and extends their application to cases with isolated mutations in the PEST degradation domain of NOTCH1, such as MCL or chronic lymphocytic leukemia (CLL).

PubMed: 32386594
DOI: 10.1016/j.chembiol.2020.04.002

実験手法

X-RAY DIFFRACTION (3.4 Å)