Structure of homodimer of TM fragment 641–685 of human receptor ErbB2 obtained by solution heteronuclear NMR in lipid bicelles
Supplemental materials for paper: Spatial structure of dimeric transmembrane domain of the growth factor receptor erbb2 presumably corresponding to the receptor active state.
The epidermal growth factor receptor, or ErbB, family is an important class of receptor tyrosine kinases involved in transmission of biochemical signals governing cell fate. The binding of peptide growth factors to the extracellular domain of the receptor triggers the dimerization of receptor monomers or a change in the relative orientation of monomers in preformed receptor dimers, leading to autophosphorylation of tyrosine residues in the cytoplasmic kinase domain. The transmembrane (TM) domains of ErbB play an active role in dimerization process.
We present the spatial structure of homodimer of recombinant TM fragment 641685 (ErbB2tm) of human receptor ErbB2 obtained by solution heteronuclear NMR in lipid DMPC/DHPC (1/4) bicelle followed by MD relaxation in explicit lipid bilayer. Constrained energy relaxation of the NMR structure of the ErbB2tm dimer was performed by molecular dynamics in hydrated explicit DMPC bilayer using the GROMACS 3.3.3 package. The 5-ns MD run for the representative model of the ErbB2tm dimer was carried out with NMR-derived intra- and intermonomeric distance restraints adapted for GROMACS by modifying from proton-proton NOE distance restraints to restraints between carbon atoms and polar protons.
The second structure is the MD simulation (1-ns MD with NMR distance restraints followed by 5-ns free molecular dynamics) for oncogenic Val659Glu-ErbB2tm mutant with protonated (uncharged) carboxyl group of Glu659 in both dimer subunits.
- ErbB2tm.pdb structure of erbb2tm dimer after MD relaxation in DMPC bilayer;
- erbb2tm_v659e.pdb structure of oncogenic mutant (Val659Glu) of erbb2tm dimer after MD relaxation in DMPC bilayer.