5ELV

Crystal structure of the GluA2 ligand-binding domain (S1S2J-L504-N775) in complex with glutamate and BPAM-521 at 1.92 A resolution

5ELV の概要

• エントリーDOI: 10.2210/pdb5elv/pdb
• 関連するPDBエントリー: 3IL1 3TDJ 3TDK 4N07 4U4S 4U4X
• 分子名称: Glutamate receptor 2,Glutamate receptor 2, SULFATE ION, GLYCEROL, ... (9 entities in total)
• 機能のキーワード: ampa receptor ligand-binding domain, bpam-521 allosteric modulation, membrane protein, fusion protein
• 由来する生物種: Rattus norvegicus (Rat); 詳細
• 細胞内の位置: Cell membrane ; Multi-pass membrane protein : P19491
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 60980.90

構造登録者

Krintel, C.,Juknaite, L.,Frydenvang, K.,Kastrup, J.S. (登録日: 2015-11-05, 公開日: 2016-05-04, 最終更新日: 2024-11-06)

主引用文献

Krintel, C.,Francotte, P.,Pickering, D.S.,Juknaite, L.,Phlsgaard, J.,Olsen, L.,Frydenvang, K.,Goffin, E.,Pirotte, B.,Kastrup, J.S.
Enthalpy-Entropy Compensation in the Binding of Modulators at Ionotropic Glutamate Receptor GluA2.
Biophys.J., 110:2397-2406, 2016

PubMed Abstract: The 1,2,4-benzothiadiazine 1,1-dioxide type of positive allosteric modulators of the ionotropic glutamate receptor A2 (GluA2) are promising lead compounds for the treatment of cognitive disorders, e.g., Alzheimer's disease. The modulators bind in a cleft formed by the interface of two neighboring ligand binding domains and act by stabilizing the agonist-bound open-channel conformation. The driving forces behind the binding of these modulators can be significantly altered with only minor substitutions to the parent molecules. In this study, we show that changing the 7-fluorine substituent of modulators BPAM97 (2) and BPAM344 (3) into a hydroxyl group (BPAM557 (4) and BPAM521 (5), respectively), leads to a more favorable binding enthalpy (ΔH, kcal/mol) from -4.9 (2) and -7.5 (3) to -6.2 (4) and -14.5 (5), but also a less favorable binding entropy (-TΔS, kcal/mol) from -2.3 (2) and -1.3 (3) to -0.5 (4) and 4.8 (5). Thus, the dissociation constants (Kd, μM) of 4 (11.2) and 5 (0.16) are similar to those of 2 (5.6) and 3 (0.35). Functionally, 4 and 5 potentiated responses of 10 μM L-glutamate at homomeric rat GluA2(Q)i receptors with EC50 values of 67.3 and 2.45 μM, respectively. The binding mode of 5 was examined with x-ray crystallography, showing that the only change compared to that of earlier compounds was the orientation of Ser-497 pointing toward the hydroxyl group of 5. The favorable enthalpy can be explained by the formation of a hydrogen bond from the side-chain hydroxyl group of Ser-497 to the hydroxyl group of 5, whereas the unfavorable entropy might be due to desolvation effects combined with a conformational restriction of Ser-497 and 5. In summary, this study shows a remarkable example of enthalpy-entropy compensation in drug development accompanied with a likely explanation of the underlying structural mechanism.

PubMed: 27276258
DOI: 10.1016/j.bpj.2016.04.032

実験手法

X-RAY DIFFRACTION (1.92 Å)