Nature of Endogenous Ligand Binding to Heme Iron in Oxygen Sensor FixL

1996 ◽  
Vol 118 (39) ◽  
pp. 9434-9435 ◽  
Author(s):  
Koji Tamura ◽  
Hiro Nakamura ◽  
Yuji Tanaka ◽  
Soichi Oue ◽  
Koki Tsukamoto ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Oxygen Sensor ◽  
Heme Iron ◽  
Endogenous Ligand

Ligand Binding Dynamics to the Heme Domain of the Oxygen Sensor Dos fromEscherichia coli

Biochemistry ◽  
2003 ◽  
Vol 42 (21) ◽  
pp. 6527-6535 ◽  
Author(s):  
Ursula Liebl ◽  
Latifa Bouzhir-Sima ◽  
Laurent Kiger ◽  
Michael C. Marden ◽  
Jean-Christophe Lambry ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Oxygen Sensor ◽  
Fromescherichia Coli ◽  
Heme Domain

Pressure effects reveal that changes in the redox states of the heme iron complexes in the sensor domains of two heme-based oxygen sensor proteins,EcDOS and YddV, have profound effects on their flexibility

FEBS Journal ◽  
2014 ◽  
Vol 281 (23) ◽  
pp. 5208-5219 ◽  
Author(s):  
Pavel Anzenbacher ◽  
Stéphane Marchal ◽  
Jan Palacký ◽  
Eva Anzenbacherová ◽  
Thomas Domaschke ◽  
...  
Keyword(s):  
Oxygen Sensor ◽  
Iron Complexes ◽  
Heme Iron ◽  
Pressure Effects ◽  
Redox States ◽  
Sensor Proteins

scholarly journals Cooperative Cobinding of Synthetic and Natural Ligands to the Nuclear Receptor PPARγ

2018 ◽  
Author(s):  
Jinsai Shang ◽  
Richard Brust ◽  
Sarah A. Mosure ◽  
Jared Bass ◽  
Paola Munoz-Tello ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Peroxisome Proliferator ◽  
Binding Modes ◽  
Endogenous Ligand ◽  
Peroxisome Proliferator Activated Receptor ◽  
X Ray Crystallography ◽  
Natural Ligands ◽  
Synthetic Ligand ◽  
Dynamics Simulations ◽  
And Function

Crystal structures of peroxisome proliferator-activated receptor gamma (PPARγ) have revealed overlapping binding modes for synthetic and natural/endogenous ligands, indicating competition for the orthosteric pocket. Here we show that cobinding of a synthetic ligand to the orthosteric pocket can push natural and endogenous PPARγ ligands (fatty acids) out of the orthosteric pocket towards an alternate ligand-binding site near the functionally important omega (Ω) loop. X-ray crystallography, NMR spectroscopy, all-atom molecular dynamics simulations, and mutagenesis coupled to quantitative functional assays reveal that synthetic ligand and fatty acid cobinding can form a “ligand link” to the Ω loop and synergistically affect the structure and function of PPARγ. These findings contribute to a growing body of evidence indicating ligand binding to nuclear receptors can be more complex than the classical one-for-one orthosteric exchange of a natural or endogenous ligand with a synthetic ligand.

scholarly journals Subpicosecond oxygen trapping in the heme pocket of the oxygen sensor FixL observed by time-resolved resonance Raman spectroscopy

2007 ◽  
Vol 104 (18) ◽  
pp. 7408-7413 ◽  
Author(s):  
Sergei G. Kruglik ◽  
Audrius Jasaitis ◽  
Klara Hola ◽  
Taku Yamashita ◽  
Ursula Liebl ◽  
...  
Keyword(s):  
Oxygen Sensor ◽  
Protein Complexes ◽  
Signal Transmission ◽  
Resonance Raman Spectroscopy ◽  
Resonance Raman ◽  
Plane Motion ◽  
Heme Iron ◽  
Time Resolved ◽  
Mutant Proteins ◽  
Sensor Protein

Dissociation of oxygen from the heme domain of the bacterial oxygen sensor protein FixL constitutes the first step in hypoxia-induced signaling. In the present study, the photodissociation of the heme-O2 bond was used to synchronize this event, and time-resolved resonance Raman (TR3) spectroscopy with subpicosecond time resolution was implemented to characterize the heme configuration of the primary photoproduct. TR3 measurements on heme-oxycomplexes are highly challenging and have not yet been reported. Whereas in all other known six-coordinated heme protein complexes with diatomic ligands, including the oxymyoglobin reported here, heme iron out-of-plane motion (doming) occurs faster than 1 ps after iron–ligand bond breaking; surprisingly, no sizeable doming is observed in the oxycomplex of the Bradyrhizobium japonicum FixL sensor domain (FixLH). This assessment is deduced from the absence of the iron–histidine band around 217 cm−1 as early as 0.5 ps. We suggest that efficient ultrafast oxygen rebinding to the heme occurs on the femtosecond time scale, thus hindering heme doming. Comparing WT oxy-FixLH, mutant proteins FixLH-R220H and FixLH-R220Q, the respective carbonmonoxy-complexes, and oxymyoglobin, we show that a hydrogen bond of the terminal oxygen atom with the residue in position 220 is responsible for the observed behavior; in WT FixL this residue is arginine, crucially implicated in signal transmission. We propose that the rigid O2 configuration imposed by this residue, in combination with the hydrophobic and constrained properties of the distal cavity, keep dissociated oxygen in place. These results uncover the origin of the “oxygen cage” properties of this oxygen sensor protein.

scholarly journals ‘CO2-ligated’ cytochrome c oxidase: characterization and comparison with the Cl- -ligated enzyme

1994 ◽  
Vol 302 (3) ◽  
pp. 821-826 ◽  
Author(s):  
A J Moody ◽  
M Richardson ◽  
J P Spencer ◽  
U Brandt ◽  
P R Rich
Keyword(s):  
Electron Transfer ◽  
Cytochrome C ◽  
Ligand Binding ◽  
Cytochrome C Oxidase ◽  
Absorption Spectra ◽  
Intramolecular Electron Transfer ◽  
Endogenous Ligand ◽  
Binding Properties ◽  
Visible Absorption ◽  
Bovine Heart

A form of fully oxidized bovine heart cytochrome c oxidase that is induced by CO2/HCO3- is described. The ligand-binding properties of this form are similar to those of Cl(-)-ligated oxidase [Moody, Cooper and Rich (1991) Biochim. Biophys. Acta 1059, 189-207]. Both bind cyanide at a rate (0.2 M-1.s-1 at pH 6.5) intermediate between the rate of binding to the fast and slow forms of the enzyme, and binding of formate to both is almost undetectable. They are also similar in showing poor reactivity with H2O2, or with CO in the presence of O2, which, with fast oxidase, induce the formation of the ‘ferryl’ and ‘peroxy’ states respectively. However, there is a clear difference in the near-u.v./visible absorption spectra of the two forms; that induced by CO2/HCO3- has a Soret maximum at 427 nm whereas Cl(-)-ligated oxidase has a Soret maximum similar to that of fast oxidase at about 424 nm. It appears that both CO2/HCO3- and Cl- are members of a class of ligands that lowers the reactivity of the binuclear centre but does not impede intramolecular electron transfer from haem a to the binuclear centre, unlike the putative endogenous ligand responsible for slow oxidase.

scholarly journals Structural basis for heme-dependent NCoR binding to the transcriptional repressor REV-ERBβ

2020 ◽  
Author(s):  
Sarah A. Mosure ◽  
Jinsai Shang ◽  
Paola Munoz-Tello ◽  
Douglas J. Kojetin
Keyword(s):  
Nmr Spectroscopy ◽  
Ligand Binding ◽  
Crystal Structures ◽  
Binding Affinity ◽  
Isothermal Titration Calorimetry ◽  
Nuclear Receptors ◽  
Structural Basis ◽  
Titration Calorimetry ◽  
Endogenous Ligand ◽  
Biochemical Assays

ABSTRACTHeme is the endogenous ligand for the constitutively repressive REV-ERB nuclear receptors, REV-ERBα (NR1D1) and REV-ERBβ (NR1D2), but how heme regulates REV-ERB activity remains unclear. While cellular studies indicate heme is required for the REV-ERBs to bind the corepressor NCoR and repress transcription, fluorescence-based biochemical assays and crystal structures suggest that heme displaces NCoR. Here, we show that heme artifactually influences detection of NCoR interaction in fluorescence-based assays. However, using fluorescence-independent methods, isothermal titration calorimetry and NMR spectroscopy, we demonstrate that heme directly increases REV-ERBβ ligand-binding domain (LBD) binding affinity for NCoR. We further report two crystal structures of REV-ERBβ LBD cobound to heme and NCoR peptides, which reveal the structural basis for heme-dependent NCoR binding to REV-ERBβ. By resolving previous contradictory biochemical, structural, and cellular studies, our findings should facilitate renewed progress toward understanding heme-dependent REV-ERB activity.

scholarly journals Exploring a new ligand binding site of G protein-coupled receptors

2018 ◽  
Vol 9 (31) ◽  
pp. 6480-6489 ◽  
Author(s):  
H. C. Stephen Chan ◽  
Jingjing Wang ◽  
Krzysztof Palczewski ◽  
Slawomir Filipek ◽  
Horst Vogel ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Binding Site ◽  
G Protein ◽  
Md Simulations ◽  
Binding Pocket ◽  
G Protein Coupled Receptors ◽  
Ligand Binding Site ◽  
Endogenous Ligand ◽  
G Protein Coupled

A new binding pocket of the endogenous ligand has been discovered by MD simulations.

scholarly journals The proximal and distal pockets of the H93G myoglobin cavity mutant bind identical ligands with different affinities: Quantitative analysis of imidazole and pyridine binding

2008 ◽  
Vol 22 (2-3) ◽  
pp. 123-141 ◽  
Author(s):  
Jing Du ◽  
Masanori Sono ◽  
John H. Dawson
Keyword(s):  
Ligand Binding ◽  
Magnetic Circular Dichroism ◽  
Sperm Whale ◽  
Heme Iron ◽  
Model Systems ◽  
Binding Affinities ◽  
Quantitative Evidence ◽  
High Affinity Binding Site ◽  
Free Heme ◽  
Exogenous Ligand

His93Gly sperm whale myoglobin (H93G Mb) has the proximal histidine ligand removed to create a cavity for exogenous ligand binding, making it a versatile template for the preparation of model heme complexes. In this study, we have measured the first and second ligand binding affinities of imidazole and pyridine to form mono- and bis-ligated ferric and ferrous H93G Mb complexes. Electronic absorption spectroscopy has been utilized to determine the binding affinities for the proximal (Kd1, first ligand) and distal (Kd2, second ligand) pockets of H93G Mb. Magnetic circular dichroism spectroscopy has been used to confirm the identity of the complexes. The binding affinities for the first ligand are one hundred- to one thousand-fold higher than those for the second ligand (Kd1«Kd2) for the same exogenous ligand. This is entirely opposite to what is seen with free heme in organic solvents whereKd1»Kd2. Thus, the proximal pocket is the high affinity binding site. The lower affinity for the distal pocket can be attributed to steric hindrance from the distal histidine. This report provides quantitative evidence for differential ligand binding affinities of the proximal and distal pockets of H93G Mb, a unique property that facilitates generation of heme iron derivatives not easily prepared with other heme model systems.

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