3MK8

The MCL-1 BH3 Helix is an Exclusive MCL-1 Inhibitor and Apoptosis Sensitizer

3MK8 の概要

• エントリーDOI: 10.2210/pdb3mk8/pdb
• 分子名称: Induced myeloid leukemia cell differentiation protein Mcl-1 (3 entities in total)
• 機能のキーワード: mcl-1, mcl-1 sahb d, staple, sahb, bcl-2 family, apoptosis, anti-apoptotic, apoptosis-apoptosis regulator complex, apoptosis/apoptosis regulator
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Membrane ; Single-pass membrane protein : Q07820 Q07820
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 20337.17

構造登録者

Stewart, M.,Fire, E.,Keating, A.E.,Walensky, L.D. (登録日: 2010-04-14, 公開日: 2010-06-23, 最終更新日: 2024-10-30)

主引用文献

Stewart, M.L.,Fire, E.,Keating, A.E.,Walensky, L.D.
The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer.
Nat.Chem.Biol., 6:595-601, 2010

PubMed Abstract: The development of selective inhibitors for discrete anti-apoptotic BCL-2 family proteins implicated in pathologic cell survival remains a formidable but pressing challenge. Such precisely tailored compounds would serve as molecular probes and targeted therapies to study and treat human diseases driven by specific anti-apoptotic blockades. In particular, MCL-1 has emerged as a major resistance factor in human cancer. By screening a library of stabilized alpha-helix of BCL-2 domains (SAHBs), we determined that the MCL-1 BH3 helix is itself a potent and exclusive MCL-1 inhibitor. X-ray crystallography and mutagenesis studies defined key binding and specificity determinants, including the capacity to harness the hydrocarbon staple to optimize affinity while preserving selectivity. MCL-1 SAHB directly targets MCL-1, neutralizes its inhibitory interaction with pro-apoptotic BAK and sensitizes cancer cells to caspase-dependent apoptosis. By leveraging nature's solution to ligand selectivity, we generated an MCL-1-specific agent that defines the structural and functional features of targeted MCL-1 inhibition.

PubMed: 20562877
DOI: 10.1038/nchembio.391

実験手法

X-RAY DIFFRACTION (2.321 Å)