Sandbox42
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This sandbox is in use until August 1, 2011 for UMass Chemistry 423. Others please do not edit this page. Thanks! Chem423 Team Projects: Understanding Drug Mechanisms
Group Members: Chris Brueckner, Daniel Roy, John Clarkson, Justin Srodulski
Contents |
N-methyl-D-aspartate (NMDA) receptor in binding complex with Ketamine
Introduction
-Try to included methods of receptor functioning.... Mention AMPA receptors, Kainate receptors, NMDA receptors, with respect to glutamate regulation, also similarities of PCP and Ketamine. Make sure to mention the Mg2+ plug in the ionotropic pore of NMDA receptors... how disruption of the ionic flow/balance affects other receptors, and the synapse as a whole.
(I can help you with this if you need me to)
Anything that seems too involved, or not closely related enough we can start throwing into the additional information section. I haven't spoken with Justin, so I have no idea how that's going.
-Chris
Overall Structure
To date, the entire X-ray or NMR crystal structure of the has not been produced. However, there are many structural subunits of NMDA that have successfully been crystallized and analyzed which provide some structural information about the NMDA receptor. The architecture of NMDA receptors is modular and is composed of multiple domains with distinct functional roles. The large extracellular region of the receptor is partitioned into two domains: an (ATD) and a (LBD) (7). Each domain consists of 8 and antiparallel . The alpha helices are located on the outside while the beta sheets are found more toward the center.
The ligand-binding domain of NMDA receptors are heterotetrameric ion channels composed of two copies of the glycine-binding NR1 subunit and two copies of the L-glutamate-binding NR2 subunit. The NR1 subunit is further divided up into splice units while the NR2 subunit has four sub-variants (NR2A-NR2D). The receptor as a whole has four general ligand binding sites (6).
The amino-terminal domain has an overall clamshell shaped structure and is notably distinct from non-NMDA receptor ATD's. The most important ATD is the NR2B ATD and it is particularly important in current research. It has been shown that the binding of Zn2+ provides neuroprotective agents without the adverse side effects that are more commonly observed with LBD agonists. NR2B ATD has the typical clamshell-like architecture composed of two domains, R1 and R2, which are tied together by three well-structured loops. There is a distinct R1–R2 domain orientation, which in NR2B ATD, is ‘twisted’ by a striking rotation of B45 and 541 compared with the R1–R2 orientation in GluR2 ATD or GluR6 ATD (7).
There are three types of sub units of an NMDA receptor, but not all receptors have the same composition of subtypes. Each subunit consists of three transmembrane segments, a P loop, and an intracellular C-terminus domain (CTD). The segments S1 and S2 in the LBD form a venus-flytrap structure and define the region for agonist recognition (6).
The first molecule is the open NMDA receptor in its natural state. The second is the closed NMDA receptor when it is bound by glutamate and co-agonist glycine. The third is the closed NMDA receptor when it is bound by Zn2+.
Drug Binding Site
(Ligand Binding Domains vs Amino Terminal Domains)
(Ketamine) -- Racemic properties, 4x stronger binding affinity for S-Ketamine (see image)
(PCP) -- include discussion of metabolites, heat activated.... Blood-brain-barrier?
(Mg2+)
(Glutamate)
(Glycine)
(D-Serine?)
Additional Features
Credits
John Clarkson: Introduction
Daniel Roy: Overall Structure
Chris Brueckner: Drug Binding Site
Justin Srodulksi: Additional Features
References
- test (PCP Metablite image)
- (Jerrold Meyer, Psychopharmacology textbook)
- (Biochem text book)
- (Ketamine-Induced NMDA Receptor Hypofunction as a Model of Memory Impairment and Psychosis)
- (The Neuropsychopharmacology of Phencyclidine: From NMDA Receptor Hypofunction to the Dopamine Hypothesis of Schizophrenia)
- http://chemwiki.ucdavis.edu/Wikitexts/Truman_Chem_421%3A_Nagan/N-Methyl-D-Aspartate_Receptor#Subunits
- Structure of the zinc-bound amino-terminal domain of the NMDA receptor NR2B subunit
