Divergent evolution of protein conformational dynamics in dihydrofolate reductase

被引:133
作者
Bhabha, Gira [1 ,2 ]
Ekiert, Damian C. [1 ,2 ]
Jennewein, Madeleine [1 ,2 ]
Zmasek, Christian M. [3 ]
Tuttle, Lisa M. [1 ,2 ]
Kroon, Gerard [1 ,2 ]
Dyson, H. Jane [1 ,2 ]
Godzik, Adam [3 ]
Wilson, Ian A. [1 ,2 ]
Wright, Peter E. [1 ,2 ]
机构
[1] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA
[2] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA
[3] Sanford Burnham Med Res Inst, Program Bioinformat & Syst Biol, La Jolla, CA USA
基金
美国国家卫生研究院;
关键词
MULTIPLE SEQUENCE ALIGNMENT; CHEMICAL-EXCHANGE; BACKBONE DYNAMICS; TRANSIENT-STATE; FLEXIBILITY; RELAXATION; CATALYSIS; LOOP; FLUCTUATIONS; SOFTWARE;
D O I
10.1038/nsmb.2676
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Molecular evolution is driven by mutations, which may affect the fitness of an organism and are then subject to natural selection or genetic drift. Analysis of primary protein sequences and tertiary structures has yielded valuable insights into the evolution of protein function, but little is known about the evolution of functional mechanisms, protein dynamics and conformational plasticity essential for activity. We characterized the atomic-level motions across divergent members of the dihydrofolate reductase (DHFR) family. Despite structural similarity, Escherichia coli and human DHFRs use different dynamic mechanisms to perform the same function, and human DHFR cannot complement DHFR-deficient E. coli cells. Identification of the primary-sequence determinants of flexibility in DHFRs from several species allowed us to propose a likely scenario for the evolution of functionally important DHFR dynamics following a pattern of divergent evolution that is tuned by cellular environment.
引用
收藏
页码:1243 / U262
页数:10
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