Evolutionary trace analysis of ionotropic glutamate receptor sequences and modeling the interactions of agonists with different NMDA receptor subunits

被引:9
作者
Blaise, MC
Sowdhamini, R
Rao, MRP
Pradhan, N [1 ]
机构
[1] Natl Inst Mental Hlth & Neurosci, Dept Psychopharmacol, Bangalore 560029, Karnataka, India
[2] UAS, NCBS, TIFR, Bangalore 560065, Karnataka, India
关键词
NMDA; ligand binding core; S1S2; segment; ET analysis; homology modeling; hydrogen bonding;
D O I
10.1007/s00894-004-0196-7
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The ionotropic N-methyl-D-aspartate (NMDA) receptor is of importance in neuronal development, functioning, and degeneration in the mammalian central nervous system. The functional NMDA receptor is a heterotetramer comprising two NR1 and two NR2 or NR3 subunits. We have carried out evolutionary trace (ET) analysis of forty ionotropic glutamate receptor (IGRs) sequences to identify and characterize the residues forming the binding socket. We have also modeled the ligand binding core (S1S2) of NMDA receptor subunits using the recently available crystal structure of NR1 subunit ligand binding core which shares similar to40% homology with other NMDA receptor subunits. A short molecular dynamics simulation of the glycine-bound form of wild-type and double-mutated (D481N; K483Q) NR1 subunit structure shows considerable RMSD at the hinge region of S1S2 segment, where pore forming transmembrane helices are located in the native receptor. It is suggested that the disruption of domain closure could affect ion-channel activation and thereby lead to perturbations in normal animal behavior. In conclusion, we identified the amino acids that form the ligand-binding pocket in many ionotropic glutamate receptors and studied their hydrogen bonded and nonbonded interaction patterns. Finally, the disruption in the S1S2 domain conformation (of NR1 subunit- crystal structure) has been studied with a short molecular dynamics simulation and correlated with some experimental observations.
引用
收藏
页码:305 / 316
页数:12
相关论文
共 48 条
[1]   Gapped BLAST and PSI-BLAST: a new generation of protein database search programs [J].
Altschul, SF ;
Madden, TL ;
Schaffer, AA ;
Zhang, JH ;
Zhang, Z ;
Miller, W ;
Lipman, DJ .
NUCLEIC ACIDS RESEARCH, 1997, 25 (17) :3389-3402
[2]  
Anson LC, 1998, J NEUROSCI, V18, P581
[3]   A prokaryotic glutamate receptor: homology modelling and molecular dynamics simulations of GluR0 [J].
Arinaminpathy, Y ;
Biggin, PC ;
Shrivastava, IH ;
Sansom, MSP .
FEBS LETTERS, 2003, 553 (03) :321-327
[4]   Molecular dynamics simulations of the ligand-binding domain of the ionotropic glutamate receptor GluR2 [J].
Arinaminpathy, Y ;
Sansom, MSP ;
Biggin, PC .
BIOPHYSICAL JOURNAL, 2002, 82 (02) :676-683
[5]   Mechanisms for activation and antagonism of an AMPA-Sensitive glutamate receptor: Crystal structures of the GluR2 ligand binding core [J].
Armstrong, N ;
Gouaux, E .
NEURON, 2000, 28 (01) :165-181
[6]   THE PROBABLE ARRANGEMENT OF THE HELICES IN G-PROTEIN-COUPLED RECEPTORS [J].
BALDWIN, JM .
EMBO JOURNAL, 1993, 12 (04) :1693-1703
[7]  
Ballard TM, 2002, J NEUROSCI, V22, P6713
[8]   Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits [J].
Chatterton, JE ;
Awobuluyi, M ;
Premkumar, LS ;
Takahashi, H ;
Talantova, M ;
Shin, Y ;
Cui, JK ;
Tu, SC ;
Kevin, ASK ;
Nakanishi, N ;
Tong, G ;
Lipton, SA ;
Zhang, DX .
NATURE, 2002, 415 (6873) :793-798
[9]   THE RELATION BETWEEN THE DIVERGENCE OF SEQUENCE AND STRUCTURE IN PROTEINS [J].
CHOTHIA, C ;
LESK, AM .
EMBO JOURNAL, 1986, 5 (04) :823-826
[10]  
CIABARRA AM, 1995, J NEUROSCI, V15, P6498