Structural determinants of ligand migration in Mycobacterium tuberculosis truncated hemoglobin O

被引:44
作者
Boechi, Leonardo [1 ]
Marti, Marcelo A. [1 ]
Milani, Mario [2 ,3 ]
Bolognesi, Martino [2 ,3 ]
Luque, F. Javier [4 ,5 ]
Estrin, Dario A. [1 ]
机构
[1] Univ Buenos Aires, Fac Ciencias Exactas & Nat, Dept Quim Inorgan Analit & Quim Fis, INQUIMAE CONICET, Buenos Aires, DF, Argentina
[2] Univ Milan, Dept Biomol Sci & Biotechnol, Milan, Italy
[3] Univ Milan, CNR INFM, Milan, Italy
[4] Univ Barcelona, Fac Farm, Dept Fisicoquim, E-08028 Barcelona, Spain
[5] Univ Barcelona, Fac Farm, Inst Biomed, E-08028 Barcelona, Spain
关键词
truncated hemoglobin; Mycobacterium tuberculosis; molecular dynamics; ligand migration; Jarzynski;
D O I
10.1002/prot.22072
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
Mycobacterium tuberculosis is the causative agent of human tuberculosis, one of the most prevalent infectious diseases in the world. Its genome hosts the glbN and glbO genes coding for two proteins, truncated hemoglobin N (trHbN) and truncated hemoglobin O (trHbO), that belong to different groups (I and 11, respectively) of the recently discovered trHb family of hemeproteins. The different expression pattern and kinetics rates constants for ligand association and NO oxidation rate suggest different functions for these proteins. Previous experimental and theoretical studies showed that, in trHbs, ligand migration along the internal tunnel cavity system is a key issue in determining the ligand-binding characteristics. The X-ray structure of trHbO has been solved and shows several internal cavities and secondary-docking sites. In this work, we present an extensive investigation of the tunnel/cavity system of M. tuberculosis trHbO by means of computer-simulation techniques. We have computed the free-energy profiles for ligand migration along three found tunnels in the oxy and deoxy w.t. and mutant trHbO proteins. Our results show that multiple-ligand migration paths are possible and that several conserved residues such as TrpG8 play a key role in the ligand-migration regulation.
引用
收藏
页码:372 / 379
页数:8
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