3D4K

Concanavalin A Complexed to a Synthetic Analog of the Trimannoside

3D4K の概要

• エントリーDOI: 10.2210/pdb3d4k/pdb
• 関連するPDBエントリー: 1CVN 1GKB
• 分子名称: Concanavalin-A, alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]methyl 2-deoxy-2-(2-hydroxyethyl)-alpha-D-mannopyranoside, MANGANESE (II) ION, ... (6 entities in total)
• 機能のキーワード: concanavalin a, conserved water, carbohydrate-protein binding, glycoprotein, lectin, manganese, metal-binding, sugar binding protein
• 由来する生物種: Canavalia ensiformis (Jack bean); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 105424.05

構造登録者

Kadirvelraj, R.,Foley, B.L.,Dyekjaer, J.D.,Woods, R.J. (登録日: 2008-05-14, 公開日: 2009-03-03, 最終更新日: 2023-08-30)

主引用文献

Kadirvelraj, R.,Foley, B.L.,Dyekjaer, J.D.,Woods, R.J.
Involvement of water in carbohydrate-protein binding: concanavalin A revisited.
J.Am.Chem.Soc., 130:16933-16942, 2008

PubMed Abstract: Ordered water molecules bound to protein surfaces, or in protein-ligand interfaces, are frequently observed by crystallography. The investigation of the impact of such conserved water molecules on protein stability and ligand affinity requires detailed structural, dynamic, and thermodynamic analyses. Several crystal structures of the legume lectin concanavalin A (Con A) bound to closely related carbohydrate ligands show the presence of a conserved water molecule that mediates ligand binding. Experimental thermodynamic and theoretical studies have examined the role of this conserved water in the complexation of Con A with a synthetic analog of the natural trisaccharide, in which a hydroxyethyl side chain replaces the hydroxyl group at the C-2 position in the central mannosyl residue. Molecular modeling earlier indicated (Clarke, C.; Woods, R. J.; Glushka, J.; Cooper, A.; Nutley, M. A.; Boons, G.-J. J. Am. Chem. Soc. 2001, 123, 12238-12247) that the hydroxyl group in this synthetic side chain could occupy a position equivalent to that of the conserved water, and thus might displace it. An interpretation of the experimental thermodynamic data, which was consistent with the displacement of the conserved water, was also presented. The current work reports the crystal structure of Con A with this synthetic ligand and shows that even though the position and interactions of the conserved water are distorted, this key water is not displaced by the hydroxyethyl moiety. This new structural data provides a firm basis for molecular dynamics simulations and thermodynamic integration calculations whose results indicate that differences in van der Waals contacts (insertion energy), rather than electrostatic interactions (charging energy) are fundamentally responsible for the lower affinity of the synthetic ligand. When combined with the new crystallographic data, this study provides a straightforward interpretation for the lower affinity of the synthetic analog; specifically, that it arises primarily from weaker interactions with the protein via the positionally perturbed conserved water. This interpretation is fully consistent with the experimental observations that the free energy of binding is enthalpy driven, that there is both less enthalpic gain and less entropic penalty for binding the synthetic ligand, relative to the natural trisaccharide, and that the entropic component does not arise from releasing an ordered water molecule from the protein surface to the bulk solvent.

PubMed: 19053475
DOI: 10.1021/ja8039663

実験手法

X-RAY DIFFRACTION (1.8 Å)