title: pH modulates the TGF-β ligands binding to the receptors: a computational analysis.
abstract: In spite of showing high sequence similarity and forming structurally similar ternary complex in vitro, the in vivo role of TGF-β1 and TGF-β3 ligands suggests against their functional redundancy and necessitates the importance for the study of the specificity of these ligands. A comparative computational analysis of binary and ternary complexes of these two ligands shows that anchor residues of ligand and receptor at TGF-β:TβR2 interface are similar in both complexes. However, the potential anchor residues of TGF-β at TGF-β:TβR1 interface are different, Tyr50 and Lys51 in TGF-β3 complex and Lys60 and Tyr6 in TGF-β1 complex. Pro55 and Asp57 of TβRI may act as anchor residues in complexes of both ligands along with Ile54 for TGF-β3 complex and Val61 for TGF-β1 complex. Arg58 of TβR1 acts as a potential hot residue for TGF-β3 ternary complex but not for TGF-β1 ternary complex formation whereas Pro55 and Phe60 may act as hot residues for both complexes. The Delphi analysis of the pH dependence of the binding energy indicates that pH has a remarkable effect on the binding energy of TβR2 to the open form of TGF-β3. Lowering of pH from 7 to 4 favors binding of the open form of TGF-β3 to TβR2. Now, apart from the residues at pH 7, residues Arg25, Lys31 and Arg94 of TGF-β3 and Asp118 and Glu119 of TβR2 also contribute significantly to the binding energy. Contrary to the binding energy of TβR2 to TGF-β3/TGF-β1, TβR1 shows appreciable pH dependence for its binding in ternary complex of TGF-β3/TGF-β1. In TGF-β3 ternary complex, the TβR1 electrostatic interaction energy disfavors complex formation at pH 7 while it is favored at pH 4.
authors.affiliation: Department of Chemistry, Indian Institute of Technology, Delhi, India; Department of Chemistry, A.M.U., Aligarh, India.
authors.forename: Shahid M
authors.initials: SM
authors.lastname: Nayeem
authors.forename: Shashank
authors.initials: S
authors.lastname: Deep
mesh_terms: D001665:Binding Sites; D019295:Computational Biology; D003198:Computer Simulation; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D020539:Sequence Analysis, Protein; D016212:Transforming Growth Factor beta / Q000737:chemistry*
chemical_list: D008024:Ligands; D016212:Transforming Growth Factor beta
keywords: anchor residues; free energy of binding; hot residues; specificity; transforming growth factor