Receptor: Difference between revisions

*The 'top' layer is composed of the <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Atd_domain/4'>amino-terminal domain(ATD)</scene>

::The small molecule <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Zk1_zoom/1'>ZK200775, a phosphonate quinoxalinedione AMPA antagonist</scene><ref>PMID: 9724812</ref>, was studied as a treatment for stroke because it had demonstrated neuroprotective efficacy in experimental models of stroke and tolerability in healthy volunteers; however, in a multicenter, double-blind, randomized, placebo-controlled phase II trial, it was found to have significant sedative effects in patients with acute stroke which precludes its further development as a neuroprotective agent<ref>PMID: 16131799</ref>.

::To help give a better idea of how the glutamate receptor is oriented on the cell surface in the membrane lipid bilayer, <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/3kg2opm_mem/11'>a slab representative of hydrophobic core of the lipid bilayer</scene> as calculated by the [http://opm.phar.umich.edu/protein.php?pdbid=3kg2 Orientations of Proteins in Membranes database] (University of Michigan, USA) is shown with the red patch of spheres indicating the boundary of the hydrophobic core closet to the outside of the cell and the dark blue patch of spheres indicating the boundary closest to the inside of the cell.

*Unanticipated is the domain swapping and crossover that occurs between the subunits interactions. In order to discuss the remarkable swapping, it is best to <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Default3kg2letter/4'>designate each subunit with a letter</scene>: <br>&nbsp;&nbsp;&nbsp; '''<span style="color:forestgreen">A</span>'''&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; '''<span style="color:red">B</span>'''&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; '''<span style="color:cornflowerblue">C</span>''' &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; '''<!--<span style="color:#FFFF80">D</span>-->D'''

As a result of the swapping and symmetry mismatch, there is subunit non-equivalence; even though all the chains are the same chemically, there are two distinct conformations of the subunits. This means there are two matching pairs of subunits.  

* <span style="color:forestgreen">Subunit '''A</span>''' is equivalent to <span style="color:cornflowerblue">Subunit '''C'''</span> (in the small structure window in this section). In the main window, a <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Atocmorph/5' target='main2NDwindow'>morph showing the equivalency of the two subunits by rotating around the axis of their symmetry</scene>.

* <span style="color:red">Subunit '''B</span>''' is equivalent to Subunit '''D''' (in the small structure window in this section). <!--<span style="color:#FFFF80">Subunit '''D'''</span>(<--says 'Subunit D' in hard-to-read gold color matching the structure)--> In the main window, a  <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Btodmorph/5' target='main2NDwindow'>morph showing the equivalency of the two subunits by rotating around the axis of their symmetry</scene>.

*The segments shown again, <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Transmem/4' target='main2NDwindow'>this time parallel to the four-fold axis</scene>.

::There is <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Transmemclosed/1'>no pore visible in the center</scene> consistent with the channel being in a closed state with the antagonist (ZK200775) bound to the LBD.

::Note <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/M3_closed_top/1' target='main2NDwindow'>the differences between the conformations of the carboxy-termini ('top') of the subunit A/C and B/D M3 segments</scene>. This is in part is why the symmetry is only approximately four-fold and is one of the several intriguing observations in regard to symmetry for this macromolecule. In fact, the location of two-fold symmetry at the ends of M3 is just above the portion that spans the membrane and is close to the last region of the structure that doesn't show four-fold symmetry as abruptly below this point everything is four-fold symmetric.

This is the largest family of receptors and includes the receptors for several hormones and slow transmitters(dopamine, metabotropic glutamate). They are composed of seven transmembrane alpha helices. The loops connecting the alpha helices form extracellular and intracellular domains. The binding-site for larger peptide ligands is usually located in the extracellular domain whereas the binding site for smaller non-peptide ligands is often located between the seven alpha helices and one extracellular loop. These receptors are coupled to different intracellular effector systems via G proteins