5ELV

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

Summary for 5ELV

• Entry DOI: 10.2210/pdb5elv/pdb
• Related: 3IL1 3TDJ 3TDK 4N07 4U4S 4U4X
• Descriptor: Glutamate receptor 2,Glutamate receptor 2, SULFATE ION, GLYCEROL, ... (9 entities in total)
• Functional Keywords: ampa receptor ligand-binding domain, bpam-521 allosteric modulation, membrane protein, fusion protein
• Biological source: Rattus norvegicus (Rat); More
• Cellular location: Cell membrane ; Multi-pass membrane protein : P19491
• Total number of polymer chains: 2
• Total formula weight: 60980.90

Authors

Krintel, C.,Juknaite, L.,Frydenvang, K.,Kastrup, J.S. (deposition date: 2015-11-05, release date: 2016-05-04, Last modification date: 2024-11-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.92 Å)