The N -methyl- D -aspartic acid (NMDA) receptor isa major target of neuroprotective therapeutic agents.The NMDA receptor belongs to the class of ligand-dependent ion channels. Activation of the NMDAreceptor requires simultaneous binding of a neuromedi-ator (glutamate) and a coagonist (glycine or D -serine).The NMDA receptor is a supramolecular structurecomposed of several NR1 and NR2 subunits [1]. In thecentral nervous system (CNS), there are several splic-ing variants of the NR1 subunit [1, 2]. There are fourisoforms of the NR2 subunit (NR2A–NR2D). Thesesubunits are encoded by different genes [3]. This causesa functional and regional heterogeneity of NMDAreceptors in the CNS. Each of the NR1 and NR2 sub-units consist of four domains: (1) an N -terminal extra-cellular modulatory domain (this domain contains apotential-independent polyamine site); (2) an agonist-or coagonist-binding site (the glycine site in NR1 andthe glutamate site in NR2); (3) a transmembranedomain forming an ion channel and incorporating mag-nesium-, zinc-, phencyclidine-, and polyamine-bindingsites (the potential-dependent site); and (4) a C -termi-nal intracellular regulatory domain.The genes encoding these subunits were cloned andsequenced in the 1990s [4, 5], thereby providing amethodological basis for comparative simulation of thetertiary structure of individual domains. A spatialmodel and mechanism of activation of ligand-bindingdomains were suggested on the basis of structuralhomology of the amino acid sequences of the agonist-binding domains of glutamate receptors (ionotropic andmetabotropic), with the amino acid sequences of tworepresentatives of the family of periplasmic bindingproteins, LBP and LIVBP, involved in amino acid andsugar transport in bacteria [6]. Approximate spatialmodels of glycine and glutamate sites of the open formof the NMDA receptor have been constructed for thefirst time by Laube et al. on the basis of homology withthe periplasmic protein LAOBP [7]. A mechanism ofbinding of the corresponding agonists and antagonistswas also suggested in [7]. It should be noted that thethree-dimensional structure of the water-solubleAMPA-sensitive glutamate receptor (AMPASGR) andits complexes with various ligands (agonists, partialagonists, and antagonists) was reconstructed in 2000using X-ray diffraction analysis [8]. Because the degreeof homology between this protein and the glutamate-binding site of the NR2 subunit is higher than thedegree of homology with bacterial proteins (~30 and~18%, respectively), it may be expected that a moreadequate model can be constructed on the basis of thispattern. Therefore, this model can be used for testingthe mechanisms of ligand binding and for screening thecomputational database of low-molecular-weight com-pounds. This screening is designed to find potential reg-ulators of ion current through NMDA receptors.The goal of this work was to construct a molecularmodel of the glutamate site of the NR2B subunit of theNMDA receptor based on the homology between itsopen and closed forms, to assess the adequacy of theconstructed model, and to use this model for studyingthe processes of binding D -2-amino-5-phosphovalericacid ( D -AP5) and glutamate (an antagonist and a natu-ral agonist, respectively).At the first stage of the study, the primary sequences ofall presently known representatives of the family of iono-tropic glutamate receptors were subjected to multiplealignment. The following sequences were aligned: NR1(protein database Swiss [9], entry code P35437), NR2A(Q12879), NR2B (Q13224), NR2C (Q14957), NR2D(Q15399), GLUR1 (P42261), GLUR2 (P42262), GLUR3(P42263), GLUR4 (P48058), GLUR5 (P39086), GLUR6(Q13002), KA1 (Q16099), KA2 (Q16478), and the pri-mary sequence AMPASGR. The ClustalX software [10]and homology matrix BLOSSUM30 were used. The pro-cedure of alignment of the query sequence with the patternsequence was performed within the framework of themultiple alignment. This procedure is shown below (con-served amino acid residues subject to mutagenesis aremarked with asterisks).