title: Computational analysis of molecular basis of 1:1 interactions of NRG-1beta wild-type and variants with ErbB3 and ErbB4.
abstract: The neuregulin/ErbB system is a growth factor/receptor cascade that has been proven to be essential in the development of the heart and the sympathetic nervous system. However, the basis of the specificity of ligand-receptor recognition remains to be elucidated. In this study, the structures of NRG-1beta/ErbB3 and NRG-1beta/ErbB4 complexes were modeled based on the available structures of the homologous proteins. The binding free energies of NRG-1beta to ErbB3 and ErbB4 were calculated using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) computational method. In addition, computational alanine-scanning mutagenesis was performed in the binding site of NRG-1beta and the difference in the binding free energies between NRG-1beta mutants and the receptors was calculated. The results specify the contribution of each residue at the interaction interfaces to the binding affinity of NRG-1beta with ErbB3 and ErbB4, identifying several important interaction residue pairs that are in agreement with previously acquired experimental data. This indicates that the presented structural models of NRG-1beta/ErbB3 and NRG-1beta/ErbB4 complexes are reliable and could be used to guide future studies, such as performing desirable mutations on NRG-1beta to increase the binding affinity and selectivity to the receptor and discovering new therapeutic agents for the treatment of heart failure.
authors.affiliation: Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, and Graduate School, Chinese Academy of Sciences, Shanghai, P.R. China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
authors.forename: Lingfei
authors.initials: L
authors.lastname: Xu
authors.forename: Suxin
authors.initials: S
authors.lastname: Zheng
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Luo
authors.forename: Jianhua
authors.initials: J
authors.lastname: Shen
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Xifu
authors.initials: X
authors.lastname: Liu
authors.forename: Mingdong
authors.initials: M
authors.lastname: Zhou
mesh_terms: D000409:Alanine; D019943:Amino Acid Substitution; D001665:Binding Sites; D017124:Conserved Sequence; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000737:chemistry / Q000378:metabolism*; D014644:Genetic Variation; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed; D020890:Neuregulin-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000737:chemistry / Q000378:metabolism*; D066247:Receptor, ErbB-4; D011994:Recombinant Proteins / Q000378:metabolism; D012997:Solvents
chemical_list: D020890:Neuregulin-1; D020033:Protein Isoforms; D011994:Recombinant Proteins; D012997:Solvents; C117467:neuregulin beta; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; D000409:Alanine