Membrane Attachment Facilitates Ligand Access to the Active Site in Monoamine Oxidase A
详细信息 查看全文
- 作者：Rossen Apostolov ; Yasushige Yonezawa ; Daron M. Standley ; Gota Kikugawa ; Yu Takano ; Haruki Nakamura
- 刊名：Biochemistry
- 出版年：2009
- 出版时间：June 30, 2009
- 年：2009
- 卷：48
- 期：25
- 页码：5864-5873
- 全文大小：1326K
- 年卷期：v.48,no.25(June 30, 2009)
- ISSN：1520-4995
文摘
Monoamine oxidase membrane enzymes are responsible for the catalytic breakdown of extra- and intracellular neurotransmitters and are targets for the development of central nervous system drugs. We analyzed the dynamics of rat MAOA by performing multiple independent molecular dynamics simulations of membrane-bound and membrane-free forms to clarify the relationship between the mechanics of the enzyme and its function, with particular emphasis on the significance of membrane attachment. Principal component analysis of the simulation trajectories as well as correlations in the fluctuations of the residues pointed to the existence of three domains that define the global dynamics of the protein. Interdomain anticorrelated movements in the membrane-bound system facilitated the relaxation of interactions between residues surrounding the substrate cavity and induced conformational changes which expanded the active site cavity and opened putative pathways for substrate uptake and product release. Such events were less pronounced in the membrane-free system due to differences in the nature of the dominant modes of motion. The presence of the lipid environment is suggested to assist in decoupling the interdomain motions, consistent with the observed reduction in enzyme activity under membrane-free conditions. Our results are also in accordance with mutational analysis which shows that modifications of interdomain hinge residues decrease the activity of rat MAOA in solution.