6VTP

Crystal structure of G16C human Galectin-7 mutant

6VTP の概要

• エントリーDOI: 10.2210/pdb6vtp/pdb
• 分子名称: Galectin-7, GLYCEROL (3 entities in total)
• 機能のキーワード: human galectin-7, g16c mutant, disulfide bond, sugar binding protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 30208.07

構造登録者

Pham, N.T.H.,Calmettes, C.,Doucet, N. (登録日: 2020-02-13, 公開日: 2021-08-25, 最終更新日: 2024-11-20)

主引用文献

Pham, N.T.H.,Letourneau, M.,Fortier, M.,Begin, G.,Al-Abdul-Wahid, M.S.,Pucci, F.,Folch, B.,Rooman, M.,Chatenet, D.,St-Pierre, Y.,Lague, P.,Calmettes, C.,Doucet, N.
Perturbing dimer interactions and allosteric communication modulates the immunosuppressive activity of human galectin-7.
J.Biol.Chem., 297:101308-101308, 2021

PubMed Abstract: The design of allosteric modulators to control protein function is a key objective in drug discovery programs. Altering functionally essential allosteric residue networks provides unique protein family subtype specificity, minimizes unwanted off-target effects, and helps avert resistance acquisition typically plaguing drugs that target orthosteric sites. In this work, we used protein engineering and dimer interface mutations to positively and negatively modulate the immunosuppressive activity of the proapoptotic human galectin-7 (GAL-7). Using the PoPMuSiC and BeAtMuSiC algorithms, mutational sites and residue identity were computationally probed and predicted to either alter or stabilize the GAL-7 dimer interface. By designing a covalent disulfide bridge between protomers to control homodimer strength and stability, we demonstrate the importance of dimer interface perturbations on the allosteric network bridging the two opposite glycan-binding sites on GAL-7, resulting in control of induced apoptosis in Jurkat T cells. Molecular investigation of G16X GAL-7 variants using X-ray crystallography, biophysical, and computational characterization illuminates residues involved in dimer stability and allosteric communication, along with discrete long-range dynamic behaviors involving loops 1, 3, and 5. We show that perturbing the protein-protein interface between GAL-7 protomers can modulate its biological function, even when the overall structure and ligand-binding affinity remains unaltered. This study highlights new avenues for the design of galectin-specific modulators influencing both glycan-dependent and glycan-independent interactions.

PubMed: 34673030
DOI: 10.1016/j.jbc.2021.101308

実験手法

X-RAY DIFFRACTION (2.3 Å)