Biotechnology and Biological Sciences Research Council (BBSRC)
BB/T005378/1
英国
Wellcome Trust
107903/Z/15/Z
英国
Medical Research Council (MRC, United Kingdom)
A652-5PY40
英国
Wellcome Trust
206175/Z/17/Z
英国
引用
ジャーナル: Nat Commun / 年: 2022 タイトル: The structural basis of Cdc7-Dbf4 kinase dependent targeting and phosphorylation of the MCM2-7 double hexamer. 著者: Almutasem Saleh / Yasunori Noguchi / Ricardo Aramayo / Marina E Ivanova / Kathryn M Stevens / Alex Montoya / S Sunidhi / Nicolas Lopez Carranza / Marcin J Skwark / Christian Speck / 要旨: The controlled assembly of replication forks is critical for genome stability. The Dbf4-dependent Cdc7 kinase (DDK) initiates replisome assembly by phosphorylating the MCM2-7 replicative helicase at ...The controlled assembly of replication forks is critical for genome stability. The Dbf4-dependent Cdc7 kinase (DDK) initiates replisome assembly by phosphorylating the MCM2-7 replicative helicase at the N-terminal tails of Mcm2, Mcm4 and Mcm6. At present, it remains poorly understood how DDK docks onto the helicase and how the kinase targets distal Mcm subunits for phosphorylation. Using cryo-electron microscopy and biochemical analysis we discovered that an interaction between the HBRCT domain of Dbf4 with Mcm2 serves as an anchoring point, which supports binding of DDK across the MCM2-7 double-hexamer interface and phosphorylation of Mcm4 on the opposite hexamer. Moreover, a rotation of DDK along its anchoring point allows phosphorylation of Mcm2 and Mcm6. In summary, our work provides fundamental insights into DDK structure, control and selective activation of the MCM2-7 helicase during DNA replication. Importantly, these insights can be exploited for development of novel DDK inhibitors.
モデルのタイプ: INSILICO MODEL In silico モデル: An ab initio initial model was generated using RELION
最終 再構成
想定した対称性 - 点群: C2 (2回回転対称) / 解像度のタイプ: BY AUTHOR / 解像度: 3.6 Å / 解像度の算出法: FSC 0.143 CUT-OFF / ソフトウェア - 名称: RELION 詳細: Body 3 of multi-body refinement of MD-(ATPgS) state III 使用した粒子像数: 73093