PDBsum entry 5elv

Membrane protein

PDB id: 5elv

Contents

Protein chains

263 a.a.

Ligands

SO4 ×4

GOL ×4

ACT ×9

5PX ×2

GLU ×2

PEG ×2

Metals

_CL ×3

Waters ×444

PDB id:

5elv

Name:

Membrane protein

Title:

Crystal structure of the glua2 ligand-binding domain (s1s2j-l504-n775) in complex with glutamate and bpam-521 at 1.92 a resolution

Structure:

Glutamate receptor 2,glutamate receptor 2. Chain: a, b. Fragment: unp residues, 413-527,unp residue, 653-797. Synonym: glur-2,ampa-selective glutamate receptor 2,glur-b,glur-k2, glutamate receptor ionotropic,ampa 2,glua2. Engineered: yes. Mutation: yes. Other_details: the protein comprises segment s1 residues 413-527, a gt linker and s2 residues 653-798.

Source:

Rattus norvegicus. Rat. Organism_taxid: 10116. Gene: gria2, glur2. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

1.92Å R-factor: 0.164 R-free: 0.209

Authors:

C.Krintel,L.Juknaite,K.Frydenvang,J.S.Kastrup

Key ref:

C.Krintel et al. (2016). Enthalpy-Entropy Compensation in the Binding of Modulators at Ionotropic Glutamate Receptor GluA2. Biophys J, 110, 2397-2406. PubMed id: 27276258 DOI: 10.1016/j.bpj.2016.04.032

Date:

05-Nov-15 Release date: 04-May-16

Protein chains

P19491  (GRIA2_RAT) -  Glutamate receptor 2 from Rattus norvegicus

Seq: 883 a.a.

Struc: 263 a.a.*

* PDB and UniProt seqs differ at 6 residue positions (black crosses)

DOI no: 10.1016/j.bpj.2016.04.032

Biophys J 110:2397-2406 (2016)

PubMed id: 27276258

Enthalpy-Entropy Compensation in the Binding of Modulators at Ionotropic Glutamate Receptor GluA2.

C.Krintel, P.Francotte, D.S.Pickering, L.Juknaitė, J.Pøhlsgaard, L.Olsen, K.Frydenvang, E.Goffin, B.Pirotte, J.S.Kastrup.

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.