PDBsum entry 5buu

Membrane protein

PDB id: 5buu

Contents

Protein chains

260 a.a.

Ligands

4V6 ×2

GLU ×2

SO4 ×5

EDO ×5

Waters ×275

PDB id:

5buu

Name:

Membrane protein

Title:

Crystal structure of the glua2 ligand-binding domain (l483y-n754s) in complex with glutamate and bpam-321 at 2.07 a resolution

Structure:

Glutamate receptor 2,glutamate receptor 2. Chain: a, b. Fragment: unp residues 413-527,unp residues 653-796. Synonym: glur-2,ampa-selective glutamate receptor 2,glur-b,glur-k2, glutamate receptor ionotropic,ampa 2,glua2,glur-2,ampa-selective glutamate receptor 2,glur-b,glur-k2,glutamate receptor ionotropic, ampa 2,glua2. Engineered: yes. Mutation: yes.

Source:

Rattus norvegicus. Norway rat. Organism_taxid: 10116. Gene: gria2, glur2. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.07Å R-factor: 0.206 R-free: 0.250

Authors:

A.P.Larsen,D.Tapken,K.Frydenvang,J.S.Kastrup

Key ref:

A.P.Larsen et al. (2016). Synthesis and Pharmacology of Mono-, Di-, and Trialkyl-Substituted 7-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides Combined with X-ray Structure Analysis to Understand the Unexpected Structure-Activity Relationship at AMPA Receptors. Acs Chem Neurosci, 7, 378-390. PubMed id: 26771108 DOI: 10.1021/acschemneuro.5b00318

Date:

04-Jun-15 Release date: 17-Feb-16

Protein chains

P19491  (GRIA2_RAT) -  Glutamate receptor 2 from Rattus norvegicus

Seq: 883 a.a.

Struc: 260 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

DOI no: 10.1021/acschemneuro.5b00318

Acs Chem Neurosci 7:378-390 (2016)

PubMed id: 26771108

Synthesis and Pharmacology of Mono-, Di-, and Trialkyl-Substituted 7-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides Combined with X-ray Structure Analysis to Understand the Unexpected Structure-Activity Relationship at AMPA Receptors.

A.P.Larsen, P.Francotte, K.Frydenvang, D.Tapken, E.Goffin, P.Fraikin, D.H.Caignard, P.Lestage, L.Danober, B.Pirotte, J.S.Kastrup.

ABSTRACT

Positive allosteric modulators of 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA)-type ionotropic glutamate receptors are promising compounds for treatment of neurological disorders, for example, Alzheimer's disease. Here, we report synthesis and pharmacological evaluation of a series of mono-, di-, or trialkyl-substituted 7-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides, comprising in total 16 new modulators. The trisubstituted compounds 7b, 7d, and 7e revealed potent activity (EC2× = 2.7-4.3 μM; concentration of compound responsible for a 2-fold increase of the AMPA mediated response) as AMPA receptor potentiators in an in vitro cellular fluorescence assay (FLIPR). The 4-cyclopropyl compound 7f was found to be considerably less potent (EC2× = 60 μM), in contrast to previously described 4-monoalkyl-substituted benzothiadiazine dioxides for which the cyclopropyl group constitutes the best choice of substituent. 7b was subjected to X-ray structural analysis in complex with the GluA2 ligand-binding domain. We propose an explanation of the unexpected structure-activity relationship of this new series of mono-, di-, and trialkyl-substituted 1,2,4-benzothiadiazine 1,1-dioxide compounds. The methyl substituent in the 3-position directs the binding mode of the 1,2,4-benzothiadiazine 1,1-dioxide (BTD) scaffold. When a methyl substituent is present in the 3-position of the BTD, additional methyl substituents in both the 2- and 4-positions increase potency, whereas introduction of a 4-cyclopropyl group does not enhance potency of 2,3,4-alkyl-substituted BTDs. A hydrogen bond donor in the 2-position of the BTD is not necessary for modulator potency.