T-state hemoglobin with four ligands bound

Marden, Michael; Kister, J.; Bohn, B.; Poyart, Claire

doi:10.1021/bi00405a041

Cited by 91 publications

(63 citation statements)

References 22 publications

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“…Ala E6(␣57) and Leu E17(␣68), that are substituted by Gly and Asn, respectively. Furthermore, several lines of evidence indicate that BZF binds specifically to fully liganded R-state human hemoglobin in a functionally relevant way (17)(18)(19)(20). We do not yet fully understand the reason why the previous solution binding studies found only a nonspecific binding of BZF with human carbonmonoxyhemoglobin (11,12).…”

Section: Structure Of Carbonmonoxyhemoglobin-bezafibrate Complex 38794mentioning

confidence: 83%

“…addition of BZF causes a decrease in the CO association rate of R-state human hemoglobin by over a factor of 4 (17,18). However, in the case of oxygen binding, uncertainty remains as to how the unfavorable steric hindrance is compensated by the formation of the hydrogen bond between the N⑀ 2 of distal His and bound oxygen (35,36).…”

Section: Structure Of Carbonmonoxyhemoglobin-bezafibrate Complex 38794mentioning

confidence: 99%

“…However, some evidence shows that this assumption is not correct. For example, previous laser flash photolysis studies of carbonmonoxyhemoglobin showed that BZF causes a decrease in the CO association rate of R-state hemoglobin by over a factor of 4 (17,18). Moreover, Coletta et al (19) measured the oxygen dissociation rate from oxyhemoglobin as a function of BZF concentration and showed that the R-state molecule has saturable binding site(s) for BZF.…”

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confidence: 99%

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Crystal Structure of Horse Carbonmonoxyhemoglobin-Bezafibrate Complex at 1.55-Å Resolution

Shibayama¹,

Miura²,

Tame³

et al. 2002

Journal of Biological Chemistry

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Bezafibrate, an antilipidemic drug, is known as a potent allosteric effector of hemoglobin. The previously proposed mechanism for the allosteric potency of this drug was that it stabilizes and constrains the T-state of hemoglobin by specifically binding to the large central cavity of the T-state. Here we report a new allosteric binding site of fully liganded R-state hemoglobin for this drug. The high resolution crystal structure of horse carbonmonoxyhemoglobin in complex with bezafibrate reveals that the bezafibrate molecule lies near the surface of the E-helix of each ␣ subunit and the complex maintains the quaternary structure of the R-state. Binding is caused by the close fit of bezafibrate into the binding pocket, which is composed of some hydrophobic residues and the heme edge, suggesting the importance of hydrophobic interactions. Upon binding of bezafibrate, the distance between Fe and the N⑀ 2 of distal His E7(␣58) is shortened by 0.22 Å in the ␣ subunit, whereas no significant structural changes are transmitted to the ␤ subunit. Oxygen equilibrium studies of R-state-locked hemoglobin with bezafibrate in a wet porous sol-gel indicate that bezafibrate selectively lowers the oxygen affinity of one type of subunit within the R-state, consistent with the structural data. These results disclose a new allosteric mechanism of bezafibrate and offer the first demonstration of how the allosteric effector interacts with R-state hemoglobin.

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Section: Structure Of Carbonmonoxyhemoglobin-bezafibrate Complex 38794mentioning

confidence: 83%

Section: Structure Of Carbonmonoxyhemoglobin-bezafibrate Complex 38794mentioning

confidence: 99%

mentioning

confidence: 99%

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Crystal Structure of Horse Carbonmonoxyhemoglobin-Bezafibrate Complex at 1.55-Å Resolution

Shibayama¹,

Miura²,

Tame³

et al. 2002

Journal of Biological Chemistry

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“…The detection bandwidth was 2 nm for the rapid kinetics but was decreased for the slower ligand dissociation kinetics to avoid ligand dissociation with the probe beam. Light transmission, detected by a photo-multiplier, was recorded at different wavelengths for up to 10 s on a Lecroy (9400 or Waverunner LT342L) oscilloscope (6,17). For slower kinetics the light transmission was rerouted to the fluorometer detection system.…”

Section: Methodsmentioning

confidence: 99%

High Pressure Enhances Hexacoordination in Neuroglobin and Other Globins

Hamdane

Kiger

Hoa

et al. 2005

Journal of Biological Chemistry

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The techniques of high applied pressure and flash photolysis have been combined to study ligand rebinding to neuroglobin (Ngb) and tomato Hb, globins that may display a His-Fe-His hexacoordination in the absence of external ligands. High pressure induces a moderate decrease in the His association rate and a large decrease in His dissociation rate, thus leading to an enhancement of the overall His affinity. The overall structural difference between penta-and hexacoordinated globins may be rather small and can be overcome by external modifications such as high pressure. Over the pressure range 0.1-700 MPa (7 kbar), the globins may show a loss of over a factor of 100 in the amplitude of the bimolecular rebinding phase after photodissociation. The kinetic data show that pressure induces a moderate increase of the rate for ligand binding from the correlated pair state (just after photodissociation) and a large (factor of 1000) decrease in rate for migration through the protein. The effect on the ligand migration phase was similar for both the external ligands (such as oxygen) as for the internal (histidine) ligand, suggesting the dominant role of protein fluctuations, rather than specific chemical barriers. Thus high pressure efficiently closes the protein migration channels; however, contrary to the effect of high viscosity, high pressure induces a greater decrease in rate for ligand migration toward the exterior (heme to the solvent) versus inward migration, as if the presence of the ligand itself induces an additional steric constraint.

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“…The bimolecular recombination rates (k"") were measured after flash photolysis with a 10-ns yttriumaluminium-garnet laser pulse delivering 160 mJ at 532 nm (Quantel). Samples were typically 50 pM heme in 100 mM Bistris, pH 6.6, 100 mM NaC1, in I-mm optical cuvettes with observation at 436 nm (Marden et al, 1988). Measurements were made for samples equilibrated with 101 kPa or 10.1 kPa CO, at different levels of photodissociation.…”

Section: Absorption Spectra Static Absorption Spectra Of the Variousmentioning

confidence: 99%

Recombinant [Pheβ63]Hemoglobin Shows Rapid Oxidation of the β Chains and Low‐Affinity, Non‐Cooperative Oxygen Binding to the α Subunits

Kiger¹,

Baudin²,

Desbois³

et al. 1997

European Journal of Biochemistry

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We have engineered αβ2 [Phe63]hemoglobin by changing the highly conserved distal histidine of the β chains to a phenylalanine. The mutant tetramer binds four high‐affinity ligands, such as CO or NO, to the ferrous form, or CN to the oxidized iron; however, it binds only two low‐affinity ligands, oxygen and azide. The absorption spectrum of the ferrous deoxy or ferric forms are not normal, displaying an enhanced absorption of the visible band near 560 nm. Half of the autooxidation process, attributed to the mutated β subunits, is over 1000‐fold faster than for Hb A. The mutant Hb exhibits non‐cooperative binding of two oxygens with an affinity about fivefold lower than those of HbA valency hybrids (αmetβ)2. Functional properties of this mutant Hb resemble those of Hb Saskatoon ([Tyr63]Hb) [Suzuki, T., Hayashi, A., Shimizu, A. & Yamamura, Y. (1966) Biochim. Biophys. Acta 127, 280–2821, Flash‐photolysis experiments also indicate non‐cooperative behaviour: the CO‐recombination kinetics were independent of the fraction dissociated. Furthermore, the amplitude of the CO bimolecular phase was the same for the (αcometβ), valency hybrid or the (αcoβco), form, suggesting mainly geminate CO‐recombination kinetics to the β chains. EPR and Resonance Raman spectra did not show evidence for a hemichrome, normally considered as a six‐coordinated iron with low‐spin character. The EPR and resonance Raman spectra for the mutated β subunits demonstrate the presence of a high‐spin compound in the ferric and deoxy ferrous forms. In particular, the ferrous mutated β subunits are penta‐coordinated. The abnormal absorption spectra are possibly due to an interaction between the porphyrin and the phenyl ring in the distal position rather than to direct binding to the iron.

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T-state hemoglobin with four ligands bound

Cited by 91 publications

References 22 publications

Crystal Structure of Horse Carbonmonoxyhemoglobin-Bezafibrate Complex at 1.55-Å Resolution

Crystal Structure of Horse Carbonmonoxyhemoglobin-Bezafibrate Complex at 1.55-Å Resolution

High Pressure Enhances Hexacoordination in Neuroglobin and Other Globins

Recombinant [Pheβ63]Hemoglobin Shows Rapid Oxidation of the β Chains and Low‐Affinity, Non‐Cooperative Oxygen Binding to the α Subunits

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