The Met852 Residue Is a Key Organizer of the Ligand-Binding Cavity of the Human Mineralocorticoid Receptor

2005 ◽  
Vol 67 (5) ◽  
pp. 1714-1722 ◽  
Author(s):  
Jérôme Fagart ◽  
Cendrine Seguin ◽  
Grégory Maurice Pinon ◽  
Marie-Edith Rafestin-Oblin
Keyword(s):  
Ligand Binding ◽  
Mineralocorticoid Receptor ◽  
Binding Cavity

scholarly journals Did evolution create a flexible ligand-binding cavity in the urokinase receptor through deletion of a plesiotypic disulfide bond?

2019 ◽  
Vol 294 (18) ◽  
pp. 7403-7418 ◽  
Author(s):  
Julie M. Leth ◽  
Haydyn D. T. Mertens ◽  
Katrine Zinck Leth-Espensen ◽  
Thomas J. D. Jørgensen ◽  
Michael Ploug
Keyword(s):  
Ligand Binding ◽  
Disulfide Bond ◽  
Urokinase Receptor ◽  
Flexible Ligand ◽  
Binding Cavity

scholarly journals Crystal Structure of the Dog Allergen Can f 6

2019 ◽  
Author(s):  
Gina M Clayton ◽  
Janice White ◽  
John W Kappler ◽  
Sanny K Chan
Keyword(s):  
Ligand Binding ◽  
Structural Similarity ◽  
Binding Pocket ◽  
Cross Reactivity ◽  
Binding Partner ◽  
Sequence Identity ◽  
Natural Ligand ◽  
Binding Cavity ◽  
Can F 1 ◽  
High Degree

AbstractLipocalins represent the most important protein family of the mammalian respiratory allergens. Four of the seven named dog allergens are lipocalins: Can f 1, Can f 2, Can f 4, and Can f 6. We present the structure of Can f 6 along with data on the biophysical and biological activity of this protein in comparison with other animal lipocalins. The Can f 6 structure displays the classic lipocalin calyx-shaped ligand binding cavity within a central β-barrel similar to other lipocalins. Despite low sequence identity between the different dog lipocalin proteins, there is a high degree of structural similarity. On the other hand, Can f 6 has a similar primary sequence to cat, horse, mouse lipocalins as well as a structure that may underlie their cross reactivity. Interestingly, the entrance to the ligand binding pocket is capped by a His instead of the usually seen Tyr that may help select its natural ligand binding partner. Our highly pure recombinant Can f 6 is able to bind to human IgE (hIgE) demonstrating biological antigenicity.

scholarly journals Molecular evolution of the switch for progesterone and spironolactone from mineralocorticoid receptor agonist to antagonist

2019 ◽  
Vol 116 (37) ◽  
pp. 18578-18583 ◽  
Author(s):  
Peter J. Fuller ◽  
Yi-Zhou Yao ◽  
Ruitao Jin ◽  
Sitong He ◽  
Beatriz Martín-Fernández ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Conformational Changes ◽  
Mineralocorticoid Receptor ◽  
Steroid Receptors ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Site Directed Mutagenesis ◽  
Structural Basis ◽  
Terrestrial Vertebrates ◽  
Terrestrial Vertebrate

The mineralocorticoid receptor (MR) is highly conserved across vertebrate evolution. In terrestrial vertebrates, the MR mediates sodium homeostasis by aldosterone and also acts as a receptor for cortisol. Although the MR is present in fish, they lack aldosterone. The MR binds progesterone and spironolactone as antagonists in human MR but as agonists in zebrafish MR. We have defined the molecular basis of these divergent responses using MR chimeras between the zebrafish and human MR coupled with reciprocal site-directed mutagenesis and molecular dynamic (MD) simulation based on the crystal structures of the MR ligand-binding domain. Substitution of a leucine by threonine in helix 8 of the ligand-binding domain of the zebrafish MR confers the antagonist response. This leucine is conserved across fish species, whereas threonine (serine in rodents) is conserved in terrestrial vertebrate MR. MD identified an interaction of the leucine in helix 8 with a highly conserved leucine in helix 1 that stabilizes the agonist conformation including the interaction between helices 3 and 5, an interaction which has previously been characterized. This switch in the MR coincides with the evolution of terrestrial vertebrates and of aldosterone synthesis. It was perhaps mandatory if the appearance of aldosterone as a specific mediator of the homeostatic salt retention was to be tolerated. The conformational changes also provide insights into the structural basis of agonism versus antagonism in steroid receptors with potential implications for drug design in this important therapeutic target.

scholarly journals Ligand binding cavity encoded as a local hydrophobicity deficiency

2020 ◽  
pp. 91-93 ◽  
Author(s):  
Mateusz Banach ◽  
Leszek Konieczny ◽  
Irena Roterman
Keyword(s):  
Ligand Binding ◽  
Binding Cavity

High-resolution structures of mutants of residues that affect access to the ligand-binding cavity of human lipocalin-type prostaglandin D synthase

2014 ◽  
Vol 70 (8) ◽  
pp. 2125-2138 ◽  
Author(s):  
Massimiliano Perduca ◽  
Michele Bovi ◽  
Mattia Bertinelli ◽  
Edoardo Bertini ◽  
Laura Destefanis ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Solvent Molecule ◽  
Triple Mutant ◽  
X Ray ◽  
Structural Work ◽  
Prostaglandin D Synthase ◽  
Binding Cavity ◽  
Human Proteins ◽  
Prostaglandin H ◽  
Small Hydrophobic

Lipocalin-type prostaglandin D synthase (L-PGDS) catalyzes the isomerization of the 9,11-endoperoxide group of PGH2(prostaglandin H2) to produce PGD2(prostaglandin D2) with 9-hydroxy and 11-keto groups. The product of the reaction, PGD2, is the precursor of several metabolites involved in many regulatory events. L-PGDS, the first member of the important lipocalin family to be recognized as an enzyme, is also able to bind and transport small hydrophobic molecules and was formerly known as β-trace protein, the second most abundant protein in human cerebrospinal fluid. Previous structural work on the mouse and human proteins has focused on the identification of the amino acids responsible and the proposal of a mechanism for catalysis. In this paper, the X-ray structures of the apo and holo forms (bound to PEG) of the C65A mutant of human L-PGDS at 1.40 Å resolution and of the double mutant C65A/K59A at 1.60 Å resolution are reported. The apo forms of the double mutants C65A/W54F and C65A/W112F and the triple mutant C65A/W54F/W112F have also been studied. Mutation of the lysine residue does not seem to affect the binding of PEG to the ligand-binding cavity, and mutation of a single or both tryptophans appears to have the same effect on the position of these two aromatic residues at the entrance to the cavity. A solvent molecule has also been identified in an invariant position in the cavity of virtually all of the molecules present in the nine asymmetric units of the crystals that have been examined. Taken together, these observations indicate that the residues that have been mutated indeed appear to play a role in the entrance–exit process of the substrate and/or other ligands into/out of the binding cavity of the lipocalin.

scholarly journals Determinants of spironolactone binding specificity in the mineralocorticoid receptor

2003 ◽  
Vol 31 (3) ◽  
pp. 573-582 ◽  
Author(s):  
FM Rogerson ◽  
YZ Yao ◽  
BJ Smith ◽  
N Dimopoulos ◽  
PJ Fuller
Keyword(s):  
Crystal Structure ◽  
Experimental Data ◽  
Amino Acids ◽  
Ligand Binding ◽  
Mineralocorticoid Receptor ◽  
Binding Specificity ◽  
Binding Pocket ◽  
Clinical Use ◽  
Ligand Binding Pocket ◽  
Binding Domains

Spironolactone is a mineralocorticoid receptor (MR) antagonist in clinical use. The compound has a very low affinity for the glucocorticoid receptor (GR). Determinants of binding specificity of spironolactone to the MR were investigated using chimeras created between the ligand-binding domains (LBDs) of the MR and the GR. These chimeras had previously been used to investigate aldosterone binding specificity to the MR. Spironolactone was able to compete strongly for [(3)H]-aldosterone and [(3)H]-dexamethasone binding to a chimera containing amino acids 804-874 of the MR, and weakly for [(3)H]-dexamethasone binding to a chimera containing amino acids 672-803 of the MR. Amino acids 804-874 were also critical for aldosterone binding specificity. Models of the MR LBD bound to aldosterone and spironolactone were created based on the crystal structure of the progesterone receptor LBD. The ligand-binding pocket of the MR LBD model consisted of 23 amino acids and was predominantly hydrophobic in nature. Analysis of this model in light of the experimental data suggested that spironolactone binding specificity is not governed by amino acids in the ligand-binding pocket.

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