Structural Basis for AMPA Receptor Activation and Ligand Selectivity: Crystal Structures of Five Agonist Complexes with the GluR2 Ligand-binding Core

2002 ◽  
Vol 322 (1) ◽  
pp. 93-109 ◽  
Author(s):  
A. Hogner ◽  
J.S. Kastrup ◽  
R. Jin ◽  
T. Liljefors ◽  
M.L. Mayer ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Crystal Structures ◽  
Ampa Receptor ◽  
Receptor Activation ◽  
Structural Basis ◽  
Ligand Selectivity ◽  
Binding Core

Structural aspects of agonism and antagonism in the oestrogen receptor

2000 ◽  
Vol 28 (4) ◽  
pp. 396-400 ◽  
Author(s):  
A. C. W. Pike ◽  
A. M. Brzozowski ◽  
J. Walton ◽  
R. E. Hubbard ◽  
T. Bonn ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Oestrogen Receptor ◽  
Three Dimensional ◽  
Receptor Activation ◽  
Structural Basis ◽  
Diverse Range ◽  
Antagonist Action ◽  
Receptor Agonists And Antagonists ◽  
Insight Into ◽  
Structural Aspects

We have determined the three-dimensional structures of both α- and β-forms of the ligand-binding domain of the oestrogen receptor (ER) in complexes with a range of receptor agonists and antagonists. Here, we summarize how these structures provide both an understanding of the ER's distinctive pharmacophore and a rationale for its ability to bind a diverse range of chemically distinct compounds. In addition, these studies provide a unique insight into the mechanisms that underlie receptor activation, as well as providing a structural basis for the antagonist action of molecules, such as raloxifene.

scholarly journals Regulation of AMPA Receptor Gating by Ligand Binding Core Dimers

Neuron ◽  
2004 ◽  
Vol 41 (3) ◽  
pp. 379-388 ◽  
Author(s):  
Michelle S Horning ◽  
Mark L Mayer
Keyword(s):  
Ligand Binding ◽  
Ampa Receptor ◽  
Binding Core

scholarly journals Rhodopsin: Structural Basis of Molecular Physiology

2001 ◽  
Vol 81 (4) ◽  
pp. 1659-1688 ◽  
Author(s):  
Santosh T. Menon ◽  
May Han ◽  
Thomas P. Sakmar
Keyword(s):  
Ligand Binding ◽  
Conformational Changes ◽  
Critical Evaluation ◽  
Binding Pocket ◽  
Receptor Activation ◽  
Structural Basis ◽  
Molecular Physiology ◽  
Movement Model ◽  
Ligand Binding Pocket ◽  
Cytoplasmic Surface

The crystal structure of rod cell visual pigment rhodopsin was recently solved at 2.8-Å resolution. A critical evaluation of a decade of structure-function studies is now possible. It is also possible to begin to explain the structural basis for several unique physiological properties of the vertebrate visual system, including extremely low dark noise levels as well as high gain and color detection. The ligand-binding pocket of rhodopsin is remarkably compact, and several apparent chromophore-protein interactions were not predicted from extensive mutagenesis or spectroscopic studies. The transmembrane helices are interrupted or kinked at multiple sites. An extensive network of interhelical interactions stabilizes the ground state of the receptor. The helix movement model of receptor activation, which might apply to all G protein-coupled receptors (GPCRs) of the rhodopsin family, is supported by several structural elements that suggest how light-induced conformational changes in the ligand-binding pocket are transmitted to the cytoplasmic surface. The cytoplasmic domain of the receptor is remarkable for a carboxy-terminal helical domain extending from the seventh transmembrane segment parallel to the bilayer surface. Thus the cytoplasmic surface appears to be approximately the right size to bind to the transducin heterotrimer in a one-to-one complex. Future high-resolution structural studies of rhodopsin and other GPCRs will form a basis to elucidate the detailed molecular mechanism of GPCR-mediated signal transduction.

scholarly journals Domain closure of the ligand-binding core of the AMPA receptor GluR2: insights from agonist and antagonist complexes

2005 ◽  
Vol 61 (a1) ◽  
pp. c234-c234
Author(s):  
C. Kasper ◽  
K. Frydenvang ◽  
B. Vestergaard ◽  
D. Sprogøe ◽  
H. Hald ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Ampa Receptor ◽  
Binding Core ◽  
Agonist And Antagonist

scholarly journals Structural basis for 2′-deoxyguanosine recognition by the 2′-dG-II class of riboswitches

2019 ◽  
Vol 47 (20) ◽  
pp. 10931-10941 ◽  
Author(s):  
Michal M Matyjasik ◽  
Robert T Batey
Keyword(s):  
Ligand Binding ◽  
Consensus Sequence ◽  
Bioinformatic Analysis ◽  
Binding Pocket ◽  
Structural Basis ◽  
Binding Core ◽  
Nucleotide Insertion ◽  
Parental Class ◽  
Purine Riboswitch ◽  
Aptamer Domain

Abstract A recent bioinformatic analysis of well-characterized classes of riboswitches uncovered subgroups unable to bind to the regulatory molecule of the parental class. Within the guanine/adenine class, seven groups of RNAs were identified that deviate from the consensus sequence at one or more of three positions directly involved purine nucleobase recognition, one of which was validated as a second class of 2′-deoxyguanosine riboswitch (called 2′-dG-II). To understand how 2′-dG-II riboswitches recognize their cognate ligand and how they differ from a previously identified class of 2′-deoxyguanosine binding riboswitches, we have solved the crystal structure of a 2′-dG-II aptamer domain bound to 2′-deoxyguanosine. This structure reveals a global architecture similar to other members of the purine riboswitch family, but contains key differences within the ligand binding core. Defining the 2′-dG-II riboswitches is a two-nucleotide insertion in the three-way junction that promotes novel base-base interactions. Unlike 2′-dG-I riboswitches, the 2′-dG-II class only requires local changes to the ligand binding pocket of the guanine/adenine class to achieve a change in ligand preference. Notably, members of the 2′-dG-II family have variable ability to discriminate between 2′-deoxyguanosine and riboguanosine, suggesting that a subset of 2′-dG-II riboswitches may bind either molecule to regulate gene expression.

Extracellular loops and ligand binding to a subfamily of Family A G-protein-coupled receptors

2007 ◽  
Vol 35 (4) ◽  
pp. 717-720 ◽  
Author(s):  
M. Wheatley ◽  
J. Simms ◽  
S.R. Hawtin ◽  
V.J. Wesley ◽  
D. Wootten ◽  
...  
Keyword(s):  
Ligand Binding ◽  
G Protein ◽  
Tertiary Structure ◽  
Large Family ◽  
Peptide Hormone ◽  
Receptor Activation ◽  
G Protein Coupled Receptors ◽  
Ligand Selectivity ◽  
Extracellular Loops ◽  
G Protein Coupled

GPCRs (G-protein-coupled receptors) are a large family of structurally related proteins which mediate their effects by coupling to G-proteins. The V1aR (V1a vasopressin receptor) is a member of a family of related GPCRs that are activated by vasopressin {AVP ([Arg8]vasopressin)}, OT (oxytocin) and related peptides. These receptors are members of a subfamily of Family A GPCRs called the neurohypophysial peptide hormone receptor family. GPCRs exhibit a conserved tertiary structure comprising a bundle of seven TM (transmembrane) helices linked by alternating ECLs (extracellular loops) and ICLs (intracellular loops). The cluster of TM helices is functionally important for ligand binding, and, furthermore, activation of GPCRs involves movement of these TM helices. Consequently, it might be assumed that the extracellular face of GPCRs is composed of peptide linkers that merely connect important TM helices. However, using a systematic mutagenesis approach and focusing on the N-terminus and the second ECL of the V1aR, we have established that these extracellular domains fulfil a range of important roles with respect to GPCR signalling, including agonist binding, ligand selectivity and receptor activation.

scholarly journals MODELLING OF 3D-STRUCTURES OF THE RARE MELANOCORTIN-1-RECEPTOR MUTATIONS ASSOCIATED TO MELANISM IN THE BANANAQUIT

2020 ◽  
Vol 26 (1) ◽  
pp. 30-41
Author(s):  
Raúl Ernesto Sedano-Cruz ◽  
Daniel Camilo Osorio
Keyword(s):  
Ligand Binding ◽  
Glutamic Acid ◽  
Dna Sequences ◽  
Receptor Activation ◽  
Color Variation ◽  
Coarse Grained ◽  
Structural Basis ◽  
Structural Constraints ◽  
Plumage Color ◽  
Melanocortin 1 Receptor

Melanism in plumage color is often associated to the single nucleotide polymorphism of the melanocortin-1-receptor (MC1R). Despite the striking association between the substitution of a Glutamic-acid by for a Lysine at position 92 on the MC1R protein and a completely black plumage, an in-depth understanding of the effect of missense mutations on the conformational change and behavior of the MC1R in the lipid bilayer caused by the absence of a crystal structure is lacking. We examine the structural basis for receptor activation using DNA sequences from the GenBank to perform in silicoprotein homology-based modeling. Our tridimensional model shows that the Alanine for a 179-Threoninesubstitution is a structural complement of the charge-reversing effect associated to the substitution of a Glutamic-acid by for a Lysine at position 92 on the MC1R. We proposed the possibility of gradual evolution in stability and electrostatic properties of the MC1R by the sequential accumulation of these two rare substitutions. These two rare substitutions further perturb physical-chemical properties that may be necessary folding requirements of the constitutively active MC1R forms without altering of ligand binding affinity. The computational coarse-grained molecular dynamics of the MC1R binding affinities to the melanocyte-stimulating hormone predicted the disparity in ligand binding amongalleles. We speculate that the disparity in structural constraints and ligand binding among the alleles within heterozygous individuals may contribute as a mechanism to the plumage color variation in the Coereba flaveola.

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