Rungsung Ikrormi, Ramaswamy Amutha
a Centre for Bioinformatics, School of Life Sciences , Pondicherry University , Puducherry 605014 , India.
J Biomol Struct Dyn. 2017 Apr;35(5):1138-1152. doi: 10.1080/07391102.2016.1173593. Epub 2016 Jul 8.
LKB1, the tumour suppressor, is found mutated in Peutz-Jeghers syndrome (PJS). The LKB1 is a serine-threonine kinase protein that is allosterically activated by the binding of STRADα and MO25α without phosphorylating the Thr212 present at activation loop. The present study aims to highlight the structural dynamics and complexation mechanism during the allosteric activation of LKB1 by these co-activators using molecular dynamics simulations. The all atom simulations performed on the complexes of LKB1 with ATP, STRADα, and MO25α for a period of 30 ns reveal that binding of STRADα and MO25α significantly stabilizes the highly flexible regions of LKB1 such as ATP binding region (β1-β2 loop), catalytic & activation loop segments and αG helix. Also, binding of STRADα and MO25α to LKB1 promotes coordinated motion between N- and C-lobes along with the catalytic & activation loops by forming H-bonds between LKB1 and co-activators, which further facilitate to establish the conserved attributes of active LKB1 such as (i) formation of salt bridge between Lys78 and Glu98, (ii) formation of stable hydrophobic R- and C-spines, and (iii) interaction between both catalytic and activation loops. Especially, the residues of LKB1 interacting with STRADα (Arg74, Glu342) and MO25α (Glu165, Pro203 and Phe204) are observed to play a significant role in stabilizing the (LKB1-ATP)-(STRADα-ATP)-MO25α complex. Overall, the present work highlighting the structural dynamics of LKB1 by the binding of allosteric co-activators is expected to provide a basic understanding on drug design specific to PJS syndrome.
肿瘤抑制因子LKB1在黑斑息肉综合征（PJS）中发生突变。LKB1是一种丝氨酸 - 苏氨酸激酶蛋白，通过与STRADα和MO25α结合而被变构激活，且不会磷酸化存在于激活环的Thr212。本研究旨在通过分子动力学模拟突出这些共激活因子对LKB1变构激活过程中的结构动力学和复合机制。对LKB1与ATP、STRADα和MO25α的复合物进行了30纳秒的全原子模拟，结果显示STRADα和MO25α的结合显著稳定了LKB1的高度灵活区域，如ATP结合区域（β1-β2环）、催化和激活环片段以及αG螺旋。此外，STRADα和MO25α与LKB1的结合通过在LKB1和共激活因子之间形成氢键，促进了N叶和C叶以及催化和激活环之间的协同运动，这进一步有助于建立活性LKB1的保守特征，如（i）Lys78和Glu98之间形成盐桥，（ii）形成稳定的疏水R-和C-棘，以及（iii）催化环和激活环之间的相互作用。特别地，观察到LKB1与STRADα（Arg74、Glu342）和MO25α（Glu165、Pro203和Phe204）相互作用的残基在稳定（LKB1-ATP）-（STRADα-ATP）-MO25α复合物中起重要作用。总体而言，本研究通过变构共激活因子的结合突出了LKB1的结构动力学，有望为针对PJS综合征的药物设计提供基本理解。
