Hemoglobin Allostery: New Views on Old Players

Miele, A.E.; Bellelli, Andrea; Brunori, Maurizio

doi:10.1016/j.jmb.2012.12.018

Cited by 14 publications

(14 citation statements)

References 49 publications

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“…Any attempt to review recent literature on Hb is doomed to failure for lack of space. Suffice it to say that between 2005 and 2015 more than 6,500 papers were published on Hb, with several new models for cooperativity put forward [70,71]. Two publications caught my eye.…”

Section: Induced Fit Vs Conformational Selectionmentioning

confidence: 99%

Adventures in cooperativity

Derewenda

2016

Postepy Biochem

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Macromolecular X-ray crystallography has undergone a dramatic and astonishing transformation since its inception in mid 1950s, almost exclusively owing to the developments in three other fields: computer science; synchrotron radiation; and molecular biology. The process of structure solution from a single crystal, provided the quality of diffraction data is adequate, has been shortened from many years to hours, if not minutes. Yet, in spite of the exponential increase in the available structural information (~120,000 structures in the Protein Data Bank today), many fundamental problems continue to be the subject of scientific controversy. This article contains personal recollections of the author, pertaining to two research projects â conducted nearly four decades apart â both of which touch upon such long standing discussion of the Monod-Wyman-Changeux theory of cooperativity (or âconformational selectionâ) vs the Koshland-Nemethy-Filmer theory of âinduced fitâ. It is dedicated to Dr. Alexander Wlodawer on his 70th birthday, with best wishes of continuing success.

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Section: Induced Fit Vs Conformational Selectionmentioning

confidence: 99%

Adventures in cooperativity

Derewenda

2016

Postepy Biochem

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“… at 2.2–2.4 Å resolution. We have recently analyzed in depth the structural constraints and weak bonds that break in going from trout HbI deoxy (T 0 ) to the CO bound state (R 4 ) . We concluded that the salt bridges broken during the allosteric transition make a significant contribution to the difference in stability between the allosteric states, but cannot account alone for the overall free energy change calculated from the O 2 binding isotherm.…”

Section: The Minimalist Allosteric Hemoglobinmentioning

confidence: 99%

“…The extraordinary feature of trout HbI is that the shape and position of the O 2 binding curve is totally independent of solvent composition: no Bohr effect, no 2,3‐bisphosphoglycerate (BPG) (or other phosphates) effect and indeed a very limited (almost zero) effect of temperature on p (O 2 ) 1/2 . Moreover there is no evidence for αβ subunit inequivalence; no significant dissociation into αβ dimers even below micromolar concentration; and a switch‐over point just above 2 ( and references therein). The dynamics of trout HbI have been extensively studied using time resolved laser spectroscopy carried out over a wide range of fractional photolysis and temperatures from 2 to 65 °C.…”

Section: The Minimalist Allosteric Hemoglobinmentioning

confidence: 99%

“…We concluded that the salt bridges broken during the allosteric transition [7,31] make a significant contribution to the difference in stability between the allosteric states, but cannot account alone for the overall free energy change calculated from the O 2 binding isotherm. Several features of the structure-function relationships have been highlighted by Miele et al [30].…”

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confidence: 95%

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Variations on the theme: allosteric control in hemoglobin

Brunori

2013

The FEBS Journal

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Conformational selection between pre‐existing structural states of an oligomeric protein was the conceptual step behind the formulation of Monod–Wyman–Changeux (MWC) allosteric theory. Variations on the basic theme of allosteric control are briefly illustrated in this paper by reference to some hemoglobins from different species whose functional properties were found to respond to specific physiological requirements. In my opinion the enormous success of the allosteric theory may be attributed not only to its efficiency in accounting for data and its formal mathematical elegance, but also because the selective mechanism conforms to the founding concept of Darwinian evolution.

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“…17,[26][27][28][29][30][31] Despite the tremendous early efforts to study the HbA allosteric modulators, relatively few studies have been reported for the allosteric modulators of HbF. The only reported study regarding the HbF allosteric modulators was carried out by Papassotiriou et al32 who investigated the oxygen affinity…”

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confidence: 99%

Phthalides serve as potent modulators to boost fetal hemoglobin induction therapy for β-hemoglobinopathies

2019

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Fetal hemoglobin (HbF) induction therapy has become the most promising strategy for treating β-hemoglobinopathies, including sickle-cell diseases and β-thalassemia. However, subtle but critical structural difference exists between HbF and normal adult hemoglobin (HbA), which inevitably leads to reduced binding of the endogenous modulator 2,3-bisphosphoglycerate (2,3-BPG) to HbF and thus increased oxygen affinity and decreased oxygen transport efficiency of HbF. We combined the oxygen equilibrium experiments, resonance Raman (RR) spectroscopy, and molecular docking modeling, and we discuss 2 phthalides, z-butylidenephthalide and z-ligustilide, that can effectively lower the oxygen affinity of HbF. They adjust it to a level closer to that of HbA and make it a more satisfactory oxygen carrier for adults. From the oxygen equilibrium curve measurements, we show that the 2 phthalides are more effective than 2,3-BPG for modulating HbF. The RR spectra show that phthalides allosterically stabilize the oxygenated HbF in the low oxygen affinity conformation, and the molecular docking modeling reveals that the 2 chosen phthalides interact with HbF via the cleft around the γ1/γ2 interface with a binding strength ∼1.6 times stronger than that of 2,3-BPG. We discuss the implications of z-butylidenephthalide and z-ligustilide in boosting the efficacy of HbF induction therapy to mitigate the clinical severities of β-hemoglobinopathies.

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Hemoglobin Allostery: New Views on Old Players

Cited by 14 publications

References 49 publications

Adventures in cooperativity

Adventures in cooperativity

Variations on the theme: allosteric control in hemoglobin

Phthalides serve as potent modulators to boost fetal hemoglobin induction therapy for β-hemoglobinopathies

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