PDBsum entry 3lsx

Transport protein

PDB id

3lsx

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Contents

			Protein chain

					258 a.a.

			Ligands

					GLU


					PZI

			Metals

					_ZN

			Waters ×351

PDB id:

3lsx

Links

Name:

Transport protein

Title:

Piracetam bound to the ligand binding domain of glua3

Structure:

Glua3 s1s2 domain. Chain: a. Engineered: yes

Source:

Rattus norvegicus, mus musculus. Rat, mouse. Organism_taxid: 10116, 10090. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.01Å

R-factor:

0.174

R-free:

0.222

Authors:

A.H.Ahmed,R.E.Oswald

Key ref:

A.H.Ahmed and R.E.Oswald (2010). Piracetam defines a new binding site for allosteric modulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors. J Med Chem, 53, 2197-2203. PubMed id: 20163115

Date:

13-Feb-10

Release date:

16-Mar-11

PROCHECK

	Headers

	References

Protein chain

P19492 (GRIA3_RAT) - Glutamate receptor 3 from Rattus norvegicus

Seq: Struc:

Seq: Struc:					888 a.a. 258 a.a.*

Protein chain

Q9Z2W9 (GRIA3_MOUSE) - Glutamate receptor 3 from Mus musculus

Seq: Struc:

Seq: Struc:					888 a.a. 258 a.a.*

Key:

Secondary structure

CATH domain

* PDB and UniProt seqs differ at 9 residue positions (black crosses)

	J Med Chem 53:2197-2203 (2010)
PubMed id: 20163115

Piracetam defines a new binding site for allosteric modulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors.
A.H.Ahmed, R.E.Oswald.

ABSTRACT

Glutamate receptors are the most prevalent excitatory neurotransmitter receptors in the vertebrate central nervous system and are important potential drug targets for cognitive enhancement and the treatment of schizophrenia. Allosteric modulators of AMPA receptors promote dimerization by binding to a dimer interface and reducing desensitization and deactivation. The pyrrolidine allosteric modulators, piracetam and aniracetam, were among the first of this class of drugs to be discovered. We have determined the structure of the ligand binding domain of the AMPA receptor subtypes GluA2 and GluA3 with piracetam and a corresponding structure of GluA3 with aniracetam. Both drugs bind to GluA2 and GluA3 in a very similar manner, suggesting little subunit specificity. However, the binding sites for piracetam and aniracetam differ considerably. Aniracetam binds to a symmetrical site at the center of the dimer interface. Piracetam binds to multiple sites along the dimer interface with low occupation, one of which is a unique binding site for potential allosteric modulators. This new site may be of importance in the design of new allosteric regulators.

Literature references that cite this PDB file's key reference

PubMed id

Reference

20713069

J.Pøhlsgaard, K.Frydenvang, U.Madsen, and J.S.Kastrup (2011).
Lessons from more than 80 structures of the GluA2 ligand-binding domain in complex with agonists, antagonists and allosteric modulators.

Neuropharmacology, 60, 135-150.

21349697

M.L.Mayer (2011).
Structure and mechanism of glutamate receptor ion channel assembly, activation and modulation.

Curr Opin Neurobiol, 21, 283-290.

The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.