The leukemia-associated AML1 (Runx1)-CBFβ complex functions as a DNA-induced molecular clamp
The leukemia-associated AML1 (Runx1)-CBFβ complex functions as a DNA-induced molecular clamp
复制标题
DOI：
10.1038/86264
复制
发表时间：
2001-04-01
期刊：
影响因子：
--
通讯作者：
Warren, AJ
中科院分区：
文献类型：
--
作者：
Bravo, J;Li, Z;Warren, AJ
我们以 2.6 埃的分辨率确定了 AML1 (Runx1) Runt 结构域 -CBF beta -DNA 三元复合物的结构，该复合物是人类白血病突变的最常见目标。该结构揭示了 Runt 结构域 DNA 结合机制在 p53 转录因子家族中是独特的。延伸的 C 端“尾”和“翼”元件采用特定的 DNA 结合构象，将磷酸盐主链夹在扭曲的 B 型 DNA 识别位点的大沟和小沟之间。此外，延伸的“尾部”介导主沟中大部分 NF-kappaB/Rel 样碱基特异性接触。该结构清楚地解释了由于人类疾病相关的白血病发生和锁骨颅骨发育不良突变导致 Runt 结构域-CBF β 复合物 DNA 结合功能丧失的分子基础。
We have determined the structure, at 2.6 Angstrom resolution, of the AML1 (Runx1) Runt domain-CBF beta -DNA ternary complex, the most common target for mutations in human leukemia. The structure reveals that the Runt domain DNA binding mechanism is unique within the p53 family of transcription factors. The extended C-terminal 'tail' and 'wing' elements adopt a specific DNA-bound conformation that clamps the phosphate backbone between the major and minor grooves of the distorted B-form DNA recognition site. Furthermore, the extended 'tail' mediates most of the NF-kappaB/Rel-like base-specific contacts in the major groove. The structure clearly explains the molecular basis for the loss of DNA binding function of the Runt domain-CBF beta complex as a consequence of the human disease-associated mutations in leukemogenesis and cleidocranial dysplasia.