pH modulates the TGF‐β ligands binding to the receptors: a computational analysis |
| |
| Authors: | Shahid M. Nayeem Shashank Deep |
| |
| Affiliation: | 1. Department of Chemistry, Indian Institute of Technology, Delhi, India;2. Department of Chemistry, A.M.U., Aligarh, India |
| |
| 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. Copyright © 2014 John Wiley & Sons, Ltd. |
| |
| Keywords: | transforming growth factor specificity hot residues anchor residues free energy of binding |
|
|
