Loop conformation and dynamics of the Escherichia coli HPPK apo-enzyme and its binary complex with MgATP
Loop conformation and dynamics of the Escherichia coli HPPK apo-enzyme and its binary complex with MgATP
复制标题
DOI：
10.1529/biophysj.105.061556
复制
发表时间：
2005-07-01
影响因子：
3.4
通讯作者：
Duan, Y
中科院分区：
文献类型：
--
作者：
Yang, R;Lee, MC;Duan, Y
Comparison of the crystallographic and NMR structures of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) suggests that the enzyme may undergo significant conformational change upon binding to its first substrate, ATP. Two of the three surface loops (loop 2 and loop 3) accounting for most of the conformational differences appear to be confined by crystal contacts, raising questions about the putative large-scale induced-fit conformational change of HPPK and the functional roles of the conserved side-chain residues on the loops. To investigate the loop dynamics in crystal-free environment, we carried out molecular dynamics and locally enhanced sampling simulations of the apo-enzyme and the HPPK center dot MgATP complex. Our simulations showed that the crystallographic B-factors underestimated the loop dynamics considerably. We found that the open-conformation of loop 3 in the binary complex is accessible to the apo-enzyme and is the favored conformation in solution phase. These results revise our previous view of HPPK-substrate interactions and the associated functional mechanism of conformational change. The lessons learned here offer valuable structural insights into the workings of HPPK and should be useful for structure-based drug design.
