Bringing Structure to Biology
The new PDBe calendar for 2019 starts with an image representing the connection and communication between nerve cells mediated by the AMPA-type glutamate receptor.
Communication is classified as a process of exchanging and/or passing of information from one person to another. This process not only occurs between humans or animals, but it also happens on the cellular level. Every minute, cells are sending and receiving millions of messages in the form of chemical signaling molecules. These chemical signals, which can be proteins or smaller molecules (e.g. steroid hormones, amino acids or ions), are produced by a “sending cell” and secreted from the cell into the extracellular space where they can reach the “target cell”. The target cells must possess the right type of receptor for the signaling molecule to “hear and understand” the particular chemical message. When a signaling molecule binds to the receptor, it alters the shape or activity of the receptor, triggering a change inside of the cell.
Within the body, cells must communicate in order to sense and respond in the correct way to their microenvironment. Errors in signaling and information processing can lead to diseases such as cancer, neurological disorders or diabetes.
AMPA glutamate receptors
AMPA glutamate receptors sense glutamate and act as transmembrane cation channels. They are named after AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), a synthetic agonist found to mimic the natural substrate. They mediate signaling, or neurotransmission, between cells in the central nervous system. Neurotransmission can be classified as a transfer of information occurring at specialized regions (synapses) between neurons (nerve cells). The synapse is a junction that permits a neuron to pass an electrical or chemical signal to another neuron or to the target effector cell (usually muscle). For the activation of the AMPA glutamate receptor, binding of the neurotransmitter glutamate is required. When the receptor is activated, it opens the membrane channel within it and allows cations to pass through. Potassium flows out of the cell and sodium flows in. As a result, a temporary depolarization of the cell membrane occurs which triggers the nerve impulse within the cell.
Binding of glutamate to the AMPA receptor causes a conformational change of the receptor leading to the opening of the ion channel allowing K+ to leave and Na+ to enter the cell.
AMPA receptors are specialized for fast excitation. In many synapses they produce electrical responses in their targets a fraction of a millisecond after being stimulated.
Structurally, the AMPA glutamate receptor is a homo- or heterotetramer built from combinations of four different subunits. Each subunit itself consists of four distinct domains: an extracellular N-terminal domain (NTD), a ligand-binding domain (LBD), a membrane-embedded transmembrane domain (TMD) that forms the ion channel, and a cytoplasmic C-terminal domain (CTD). These four domains are grouped into 2 regions. The extracellular region (ECR), includes NTD, LBD and CTD domains, and covers the vast majority of the receptor. The second region is formed by TMD which spans the cell membrane and acts as an ion channel.
Structure of a GluA2 tetramer (PDB entry 3KG2) coloured by individual polypeptide chains.
In the PDB archive there are structures of the whole receptor (for example PDB entries 5IDE or 5WEO) and just its isolated domains (for example PDB entries 5YBG and 6FAZ). The first AMPA glutamate receptor structure to be solved was the ligand-binding subunit GluA2 (GluR2) (PDB entry 1GR2, published in 1998). Many of the structures reveal the shape of the receptor, or its isolated domains and show the mechanism of glutamate, or agonist binding. CryoEM studies have shed light into the mechanism of ion channel gate opening (for example in PDB entries 5WEL and 6DM0).
A drug target
The AMPA receptor is a target for drugs to treat diseases such as amyotrophic lateral sclerosis, epilepsy, ischemia or Alzheimer’s and the PDB contains structures of the AMPA glutamate receptor with these selective inhibitors bound (for example PDB entry 4GXS contains the molecule kaitocephalin and PDB entry 5ILF has the anti-epiliptic drug Perampanel bound). These can either trap the channel in an opened state, for example PDB entry 6DM1 with the diuretic and anti-hypertensice cyclothiazide bound, or a closed state, both of which inhibit the function of the channel.
About the artwork
A structure solved by CryoEM (PDB entry 5IDE) was used as an inspiration for the January artwork in our calendar. The image (acrylic on canvas) by Natalia Heirman from Stephen Perse Foundation represents the importance of the connection and communication between cells for their proper function extrapolated to human beings.