Structural insights into NMDA ionotropic glutamate receptors via molecular modelling

被引:8
作者
Chohan, KK [1 ]
Wo, ZG [1 ]
Oswald, RE [1 ]
Sutcliffe, MJ [1 ]
机构
[1] Univ Leicester, Dept Chem, Leicester LE1 7RH, Leics, England
关键词
agonist binding; selectivity; cation channel;
D O I
10.1007/PL00010721
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
Structural models have been produced for the agonist binding and transmembrane domains of two NMDA ionotropic glutamate receptors: homomeric NMDA-R2C and heteromeric NMDA-R1/R2C. These models-produced using homology modelling techniques in conjunction with distance restraints derived from the accessibility of substituted cysteines-have aided our understanding of (1) ligand selectivity and (2) channel activity. The model of the agonist binding domain of NMDA-R2C indicates that T691 forms an essential hydrogen bond with glutamate ligand. This interaction is absent in the NMDA-R1 model-where a valine replaces the threonine-explaining why NMDA-R1 binds glycine rather than glutamate. For the transmembrane region, the models suggest that a number of positive residues, located in the cytoplasmic loop between the M1 and M2 segments, create a large electrostatic energy barrier that could explain why homomeric NMDA-R2C channels are non-functional. Introducing NMDA-R1 to form heteromeric NMDA-R1/R2C channels is predicted to rescue channel activity because the corresponding region in NMDA-R1 contains negative residues that more than compensate for the electrostatic energy barrier in NMDA-R2C. These studies suggest that replacing the positively charged region in the M1-M2 loop of NMDA-R2C with the corresponding negatively charged region of NMDA-R1 could transform NMDA-R2C into a functional homomeric channel.
引用
收藏
页码:16 / 25
页数:10
相关论文
共 58 条
[1]  
Anson LC, 1998, J NEUROSCI, V18, P581
[2]   Structure of a glutamate-receptor ligand-binding core in complex with kainate [J].
Armstrong, N ;
Sun, Y ;
Chen, GQ ;
Gouaux, E .
NATURE, 1998, 395 (6705) :913-917
[3]   ALSCRIPT - A TOOL TO FORMAT MULTIPLE SEQUENCE ALIGNMENTS [J].
BARTON, GJ .
PROTEIN ENGINEERING, 1993, 6 (01) :37-40
[4]   NMDAR channel segments forming the extracellular vestibule inferred from the accessibility of substituted cysteines [J].
Beck, C ;
Wollmuth, LP ;
Seeburg, PH ;
Sakmann, B ;
Kuner, T .
NEURON, 1999, 22 (03) :559-570
[5]   TOPOLOGY PROFILE FOR A GLUTAMATE-RECEPTOR - 3 TRANSMEMBRANE DOMAINS AND A CHANNEL-LINING REENTRANT MEMBRANE LOOP [J].
BENNETT, JA ;
DINGLEDINE, R .
NEURON, 1995, 14 (02) :373-384
[6]   PROTEIN DATA BANK - COMPUTER-BASED ARCHIVAL FILE FOR MACROMOLECULAR STRUCTURES [J].
BERNSTEIN, FC ;
KOETZLE, TF ;
WILLIAMS, GJB ;
MEYER, EF ;
BRICE, MD ;
RODGERS, JR ;
KENNARD, O ;
SHIMANOUCHI, T ;
TASUMI, M .
JOURNAL OF MOLECULAR BIOLOGY, 1977, 112 (03) :535-542
[7]   N-1-dansyl-spermine and N-1-(n-octanesulfonyl)-spermine, novel glutamate receptor antagonists: Block and permeation of N-methyl-D-aspartate receptors [J].
Chao, J ;
Seiler, N ;
Renault, J ;
Kashiwagi, K ;
Masuko, T ;
Igarashi, K ;
Williams, K .
MOLECULAR PHARMACOLOGY, 1997, 51 (05) :861-871
[8]   THE RELATION BETWEEN THE DIVERGENCE OF SEQUENCE AND STRUCTURE IN PROTEINS [J].
CHOTHIA, C ;
LESK, AM .
EMBO JOURNAL, 1986, 5 (04) :823-826
[9]   JPred: a consensus secondary structure prediction server [J].
Cuff, JA ;
Clamp, ME ;
Siddiqui, AS ;
Finlay, M ;
Barton, GJ .
BIOINFORMATICS, 1998, 14 (10) :892-893
[10]  
Dingledine R, 1999, PHARMACOL REV, V51, P7