Intersegment hydrogen bonds as possible structural determinants of the N/Q/R site in glutamate receptors.
Specific electrophysiological and pharmacological properties of ionic channels in NMDA, AMPA, and kainate subtypes of ionotropic glutamate receptors (GluRs) are determined by the Asn (N), Gln (Q), and Arg (R) residues located at homologous positions of the pore-lining M2 segments (the N/Q/R site). Presumably, the N/Q/R site is located at the apex of the reentrant membrane loop and forms the narrowest constriction of the pore. Although the shorter Asn residues are expected to protrude in the pore to a lesser extent than the longer Gln residues, the effective dimension of the NMDA channel (corresponding to the size of the largest permeant organic cation) is, surprisingly, smaller than that of the AMPA channel. To explain this paradox, we propose that the N/Q/R residues form macrocyclic structures (rings) stabilized by H-bonds between a NH(2) group in the side chain of a given M2 segment and a C==O group of the main chain in the adjacent M2 segment. Using Monte Carlo minimization, we have explored conformational properties of the rings. In the Asn, but not in the Gln ring, the side-chain oxygens protruding into the pore may facilitate ion permeation and accept H-bonds from the blocking drugs. In this way, the model explains different electrophysiological and pharmacological properties of NMDA and non-NMDA GluR channels. The ring of H-bonded polar residues at the pore narrowing resembles the ring of four Thr(75) residues observed in the crystallographic structure of the KcsA K(+) channel.
Tikhonov
D B
DB
Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, St. Petersburg 194223, Russia. tikhonov@vv3977.spb.edu
Zhorov
B S
BS
Magazanik
L G
LG
D001120:Arginine / Q000737:chemistry / Q000378:metabolism*; D001216:Asparagine / Q000737:chemistry / Q000378:metabolism*; D001224:Aspartic Acid / Q000378:metabolism; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry / Q000378:metabolism; D005973:Glutamine / Q000737:chemistry / Q000378:metabolism*; D006860:Hydrogen Bonding; D007700:Kinetics; D008958:Models, Molecular; D009010:Monte Carlo Method; D010100:Oxygen / Q000378:metabolism; D011487:Protein Conformation; D018091:Receptors, AMPA / Q000737:chemistry / Q000378:metabolism; D017470:Receptors, Glutamate / Q000737:chemistry* / Q000378:metabolism*; D018092:Kainic Acid Receptors / Q000737:chemistry / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000378:metabolism; D055672:Static Electricity
D001120:Arginine; D001216:Asparagine; D001224:Aspartic Acid; D002118:Calcium; D018691:Excitatory Amino Acid Antagonists; D005973:Glutamine; D010100:Oxygen; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate