PT  - JOURNAL ARTICLE
AU  - Mizukoshi, Yumiko
AU  - Takeuchi, Koh
AU  - Tokunaga, Yuji
AU  - Matsuo, Hitomi
AU  - Imai, Misaki
AU  - Fujisaki, Miwa
AU  - Kamoshida, Hajime
AU  - Takizawa, Takeshi
AU  - Hanzawa, Hiroyuki
AU  - Shimada, Ichio
TI  - Targeting the cryptic sites: NMR-based strategy to improve protein druggability by controlling the conformational equilibrium
AID  - 10.1126/sciadv.abd0480
DP  - 2020 Oct 01
TA  - Science Advances
PG  - eabd0480
VI  - 6
IP  - 40
4099  - http://advances.sciencemag.org/content/6/40/eabd0480.short
4100  - http://advances.sciencemag.org/content/6/40/eabd0480.full
SO  - Sci Adv2020 Oct 01; 6
AB  - Cryptic ligand binding sites, which are not evident in the unligated structures, are beneficial in tackling with difficult but attractive drug targets, such as protein-protein interactions (PPIs). However, cryptic sites have thus far not been rationally pursued in the early stages of drug development. Here, we demonstrated by nuclear magnetic resonance that the cryptic site in Bcl-xL exists in a conformational equilibrium between the open and closed conformations under the unligated condition. While the fraction of the open conformation in the unligated wild-type Bcl-xL is estimated to be low, F143W mutation that is distal from the ligand binding site can substantially elevate the population. The F143W mutant showed a higher hit rate in a phage-display peptide screening, and the hit peptide bound to the cryptic site of the wild-type Bcl-xL. Therefore, by controlling the conformational equilibrium in the cryptic site, the opportunity to identify a PPI inhibitor could be improved.