New look at hemoglobin allostery.
Ontology highlight
ABSTRACT:
SUBMITTER: Yuan Y
PROVIDER: S-EPMC4507747 | biostudies-literature | 2015 Feb
REPOSITORIES: biostudies-literature
Publications
New look at hemoglobin allostery.
Yuan Yue Y Tam Ming F MF Simplaceanu Virgil V Ho Chien C
Chemical reviews 20150121 4
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Project description:This chapter reviews how allosteric (heterotrophic) effectors and natural mutations impact hemoglobin (Hb) primary physiological function of oxygen binding and transport. First, an introduction about the structure of Hb is provided, including the ensemble of tense and relaxed Hb states and the dynamic equilibrium of Hb multistate. This is followed by a brief review of Hb variants with altered Hb structure and oxygen binding properties. Finally, a review of different endogenous and exogenous allosteric effectors of Hb is presented with particular emphasis on the atomic interactions of synthetic ligands with altered allosteric function of Hb that could potentially be harnessed for the treatment of diseases.
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Project description:Hemoglobin is a complex system that undergoes conformational changes in response to oxygen, allosteric effectors, mutations, and environmental changes. Here, we study allostery and polymerization of hemoglobin and its variants by application of two previously described methods: (i) AllosMod for simulating allostery dynamics given two allosterically related input structures and (ii) a machine-learning method for dynamics- and structure-based prediction of the mutation impact on allostery (Weinkam et al. J. Mol. Biol. 2013, 425, 647-661), now applicable to systems with multiple coupled binding sites, such as hemoglobin. First, we predict the relative stabilities of substates and microstates of hemoglobin, which are determined primarily by entropy within our model. Next, we predict the impact of 866 annotated mutations on hemoglobin's oxygen binding equilibrium. We then discuss a subset of 30 mutations that occur in the presence of the sickle cell mutation and whose effects on polymerization have been measured. Seven of these HbS mutations occur in three predicted druggable binding pockets that might be exploited to directly inhibit polymerization; one of these binding pockets is not apparent in the crystal structure, but only in structures generated by AllosMod. For the 30 mutations, we predict that mutation-induced conformational changes within a single tetramer tend not to significantly impact polymerization; instead, these mutations more likely impact polymerization by directly perturbing a polymerization interface. Finally, our analysis of allostery allows us to hypothesize why hemoglobin evolved to have multiple subunits and a persistent low frequency sickle cell mutation.
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Project description:IntroductionSickle cell disease (SCD) is a debilitating inherited disorder that affects millions worldwide. Four novel SCD therapeutics have been approved, including the hemoglobin (Hb) modulator Voxelotor.Areas coveredThis review provides an overview of discovery efforts toward modulating Hb allosteric behavior as a treatment for SCD, with a focus on aromatic aldehydes that increase Hb oxygen affinity to prevent the primary pathophysiology of hypoxia-induce erythrocyte sickling.Expert opinionThe quest to develop small molecules, especially aromatic aldehydes, to modulate Hb allosteric properties for SCD began in the 1970s; however, early promise was dogged by concerns that stalled support for research efforts. Persistent efforts eventually culminated in the discovery of the anti-sickling agent 5-HMF in the 2000s, and reinvigorated interest that led to the discovery of vanillin analogs, including Voxelotor, the first FDA approved Hb modulator for the treatment of SCD. With burgeoning interest in the field of Hb modulation, there is a growing landscape of intellectual property, including drug candidates at various stages of preclinical and clinical investigations. Hb modulators could provide not only the best chance for a highly effective oral therapy for SCD, especially in the under-developed world, but also a way to treat a variety of other human conditions.
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