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.

Structural Aspects of Magnetic Coupling in CaCu3Mn4O12 and CaCu3Ti4P12

2002 ◽  
Vol 718 ◽  
Author(s):  
M. D. Johannes ◽  
W. E. Pickett ◽  
R. Weht
Keyword(s):  
First Principles ◽  
Exchange Coupling ◽  
Density Functional ◽  
Energy Gap ◽  
Three Dimensional ◽  
Magnetic Coupling ◽  
Superexchange Coupling ◽  
Distinct Temperature ◽  
Insight Into ◽  
Structural Aspects

AbstractTwo perovskite-derived materials, CaCu3Mn4O12, have drawn much recent interest due to their magnetoresistive, dielectric, and mafnetoelectronic characteristics. Here we present initial theoretical insights into each of these points, based on first principles, density functional based calculations. Our results predict CCMO to have a spin-asymmetric energy gap, which leads to distinct temperature- and magnetic field-dependent changes in properties, and helps to account for its observed negative magnetoresistivity. We have studied CCTO primarily to gain insight into the exchange coupling in both these compounds, where the conventional superexchange coupling vanishes by symmetry for both nearest and next nearest Cu-Cu neighbors, a consequence of the structure. In CCTO, it is necessary to go 5th Cu-Cu neighbors to obstain a (superexchange) coupling that can provide the coupling necessary to give three dimensional order. Non-superexchange mechanisms may be necessary to describe the magnetic coupling in this structural clss.

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 Structural Basis of the Enhanced Pollutant-Degrading Capabilities of an Engineered Biphenyl Dioxygenase

2016 ◽  
Vol 198 (10) ◽  
pp. 1499-1512 ◽  
Author(s):  
Sonali Dhindwal ◽  
Leticia Gomez-Gil ◽  
David B. Neau ◽  
Thi Thanh My Pham ◽  
Michel Sylvestre ◽  
...  
Keyword(s):  
Polychlorinated Biphenyl ◽  
Three Dimensional ◽  
Binding Pocket ◽  
Degradation Pathway ◽  
Dimensional Structure ◽  
Structural Basis ◽  
Biphenyl Dioxygenase ◽  
Pcb Congeners ◽  
Biphenyl Degradation ◽  
Insight Into

ABSTRACTBiphenyl dioxygenase, the first enzyme of the biphenyl catabolic pathway, is a major determinant of which polychlorinated biphenyl (PCB) congeners are metabolized by a given bacterial strain. Ongoing efforts aim to engineer BphAE, the oxygenase component of the enzyme, to efficiently transform a wider range of congeners. BphAEII9, a variant of BphAELB400in which a seven-residue segment,335TFNNIRI341, has been replaced by the corresponding segment of BphAEB356,333GINTIRT339, transforms a broader range of PCB congeners than does either BphAELB400or BphAEB356, including 2,6-dichlorobiphenyl, 3,3′-dichlorobiphenyl, 4,4′-dichlorobiphenyl, and 2,3,4′-trichlorobiphenyl. To understand the structural basis of the enhanced activity of BphAEII9, we have determined the three-dimensional structure of this variant in substrate-free and biphenyl-bound forms. Structural comparison with BphAELB400reveals a flexible active-site mouth and a relaxed substrate binding pocket in BphAEII9that allow it to bind different congeners and which could be responsible for the enzyme's altered specificity. Biochemical experiments revealed that BphAEII9transformed 2,3,4′-trichlorobiphenyl and 2,2′,5,5′-tetrachlorobiphenyl more efficiently than did BphAELB400and BphAEB356. BphAEII9also transformed the insecticide dichlorodiphenyltrichloroethane (DDT) more efficiently than did either parental enzyme (apparentkcat/Kmof 2.2 ± 0.5 mM−1s−1, versus 0.9 ± 0.5 mM−1s−1for BphAEB356). Studies of docking of the enzymes with these three substrates provide insight into the structural basis of the different substrate selectivities and regiospecificities of the enzymes.IMPORTANCEBiphenyl dioxygenase is the first enzyme of the biphenyl degradation pathway that is involved in the degradation of polychlorinated biphenyls. Attempts have been made to identify the residues that influence the enzyme activity for the range of substrates among various species. In this study, we have done a structural study of one variant of this enzyme that was produced by family shuffling of genes from two different species. Comparison of the structure of this variant with those of the parent enzymes provided an important insight into the molecular basis for the broader substrate preference of this enzyme. The structural and functional details gained in this study can be utilized to further engineer desired enzymatic activity, producing more potent enzymes.

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.

scholarly journals Thermophoretic analysis of ligand-specific conformational states of the inhibitory glycine receptor embedded in copolymer nanodiscs

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Max Bernhard ◽  
Bodo Laube
Keyword(s):  
Ligand Binding ◽  
Partial Agonist ◽  
Glycine Receptor ◽  
Three Dimensional ◽  
Receptor Activation ◽  
Cell System ◽  
Activation Mechanism ◽  
Hek293 Cells ◽  
Dimensional Structure ◽  
Conformational States

Abstract The glycine receptor (GlyR), a member of the pentameric ligand-gated ion channel family (pLGIC), displays remarkable variations in the affinity and efficacy of the full agonist glycine and the partial agonist taurine depending on the cell system used. Despite detailed insights in the GlyR three-dimensional structure and activation mechanism, little is known about conformational rearrangements induced by these agonists. Here, we characterized the conformational states of the α1 GlyR upon binding of glycine and taurine by microscale thermophoresis expressed in HEK293 cells and Xenopus oocytes after solubilization in amphipathic styrene-maleic acid copolymer nanodiscs. Our results show that glycine and taurine induce different conformational transitions of the GlyR upon ligand binding. In contrast, the variability of agonist affinity is not mediated by an altered conformational change. Thus, our data shed light on specific agonist induced conformational features and mechanisms of pLGIC upon ligand binding determining receptor activation in native environments.

A Mutation in the Extracellular Cysteine-Rich Repeat Region of the β3 Subunit Activates Integrins IIbβ3 and Vβ3

Blood ◽  
1999 ◽  
Vol 93 (8) ◽  
pp. 2559-2568 ◽  
Author(s):  
Hirokazu Kashiwagi ◽  
Yoshiaki Tomiyama ◽  
Seiji Tadokoro ◽  
Shigenori Honda ◽  
Masamichi Shiraga ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Structural Changes ◽  
Chinese Hamster ◽  
Receptor Activation ◽  
Single Amino Acid ◽  
Structural Basis ◽  
Relevant Variable ◽  
High Affinity ◽  
293 Cells ◽  
Inside Out

Abstract Inside-out signaling regulates the ligand-binding function of integrins through changes in receptor affinity and/or avidity. For example, IIbβ3 is in a low-affinity/avidity state in resting platelets, and activation of the receptor by platelet agonists enables fibrinogen to bind. In addition, certain mutations and truncations of the integrin cytoplasmic tails are associated with a high-affinity/avidity receptor. To further evaluate the structural basis of integrin activation, stable Chinese hamster ovary (CHO) cell transfectants were screened for high-affinity/avidity variants of IIbβ3. One clone (AM-1) expressed constitutively active IIbβ3, as evidenced by (1) binding of soluble fibrinogen and PAC1, a ligand-mimetic antiIIbβ3antibody; and (2) fibrinogen-dependent cell aggregation. Sequence analysis and mutant expression in 293 cells proved that a single amino acid substitution in the cysteine-rich, extracellular portion of β3(T562N) was responsible for receptor activation. In fact, T562N also activated Vβ3, leading to spontaneous binding of soluble fibrinogen to 293 cells. In contrast, neither T562A nor T562Q activated IIbβ3, suggesting that acquisition of asparagine at residue 562 was the relevant variable. T562N also led to aberrant glycosylation of β3, but this was not responsible for the receptor activation. The binding of soluble fibrinogen to IIbβ3(T562N) was not sufficient to trigger tyrosine phosphorylation of pp125FAK, indicating that additional post-ligand binding events are required to activate this protein tyrosine kinase during integrin signaling. These studies have uncovered a novel gain-of-function mutation in a region of β3 intermediate between the ligand-binding region and the cytoplasmic tail, and they suggest that this region is involved in integrin structural changes during inside-out signaling.

scholarly journals Functional Characterization and Structural Modeling of Obesity Associated Mutations in the Melanocortin 4 Receptor

Endocrinology ◽  
2008 ◽  
Vol 150 (1) ◽  
pp. 114-125 ◽  
Author(s):  
Karen Tan ◽  
Irina D. Pogozheva ◽  
Giles S. H. Yeo ◽  
Dirk Hadaschik ◽  
Julia M. Keogh ◽  
...  
Keyword(s):  
Cell Surface ◽  
Ligand Binding ◽  
Functional Characterization ◽  
Structural Modeling ◽  
Receptor Activation ◽  
Cell Surface Expression ◽  
Structural Basis ◽  
Conformational Rearrangement ◽  
Mc4r Gene ◽  
Melanocortin 4 Receptor

Mutations in the melanocortin 4 receptor (MC4R) gene are the most common known cause of monogenic human obesity. The MC4R gene was sequenced in 2000 subjects with severe early-onset obesity. We detected seven different nonsense and 19 nonsynonymous mutations in a total of 94 probands, some of which have been reported previously by others. We functionally characterized the 11 novel obesity associated missense mutations. Seven of these mutants (L54P, E61K, I69T, S136P, M161T, T162I, and I269N) showed impaired cell surface trafficking, reduced level of maximal binding of the radioligand [125I]NDP-MSH, and reduced ability to generate cAMP in response to ligand. Four mutant MC4Rs (G55V, G55D, S136F, and A303T) displayed cell surface expression and agonist binding similar to the wild-type receptor but showed impaired cAMP production, suggesting that these residues are likely to be critical for conformational rearrangement essential for receptor activation. Homology modeling of these mutants using a model of MC4R based on the crystal structure of the β2-adrenoreceptor was used to provide insights into the possible structural basis for receptor dysfunction. Transmembrane (TM) domains 1, 3, 6, 7, and peripheral helix 8 appear to participate in the agonist-induced conformational rearrangement necessary for coupling of ligand binding to signaling. We conclude that G55V, G55D, S136F, and A303T mutations are likely to strengthen helix-helix interactions between TM1 and TM2, TM3 and TM6, and TM7 and helix 8, respectively, preventing relative movement of these helices during receptor activation. The combination of functional studies and structural modeling of naturally occurring pathogenic mutations in MC4R can provide valuable information regarding the molecular mechanism of MC4R activation and its dysfunction in human disease. Among obesity-associated melanocortin-4 receptor mutations, four transmembrane domains and peripheral helix 8 are necessary for coupling of ligand binding to signaling.

Overview of the structural basis for transcription regulation by nuclear hormone receptors

2004 ◽  
Vol 40 ◽  
pp. 27-39 ◽  
Author(s):  
Raj Kumar ◽  
Betty H Johnson ◽  
E Brad Thompson
Keyword(s):  
Dna Binding ◽  
Ligand Binding ◽  
Hormone Receptors ◽  
Current Knowledge ◽  
Three Dimensional ◽  
Nuclear Hormone Receptors ◽  
Dimensional Structure ◽  
Structural Basis ◽  
Three Dimensional Structure ◽  
Functional Regions

The mechanism of action of the nuclear hormone receptors (NHRs) as gene-regulatory molecules has become a major focus of current biological interest. NHRs belong to the superfamily of ligand-activated transcription factors, which are involved in the regulation of homoeostasis, reproduction, development and differentiation. To fully understand their functions, it is important to know the functional three-dimensional structure of these proteins. Molecular cloning and structure-function analyses have revealed that NHRs commonly have three functional regions: the N-terminal, DNA-binding and ligand-binding domains. Structures of some of these domains expressed independently have been solved. However, to date the three-dimensional structure remains unknown for full-length and even for any two domains together of any NHR family member. The available structures nevertheless begin to give clues of how site-specific DNA binding takes place, and how ligand binding alters the ligand-binding domain, consequently affecting potential interactions of the NHRs with co-activators/co-repressors and other components of basal transcriptional machinery. However, precisely how signals from a ligand through its NHR are passed to specific genes is still unknown. Herein, we present a broad overview of current knowledge on the structure and functions of the NHRs.

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