Due to the poor aqueous solubility of retinoids, evolution has tuned their binding to cellular proteins to address specialized physiological roles by modulating uptake, storage, and delivery to specific targets. With the aim to disentangle the structure-function relationships in these proteins and disclose clues for engineering selective carriers, the binding mechanism of the two most abundant retinol-binding isoforms was explored by using enhanced sampling molecular dynamics simulations and surface plasmon resonance. The distinctive dynamics of the entry portal site in the holo species was crucial to modulate retinol dissociation. Remarkably, this process is controlled to a large extent by the replacement of Ile by Leu in the two isoforms, thus suggesting that fine control of ligand release can be achieved through a rigorous selection of conservative mutations in accessory sites.

Modulating Ligand Dissociation through Methyl Isomerism in Accessory Sites: Binding of Retinol to Cellular Carriers / Estarellas, Carolina; Scaffidi, Salvatore; Saladino, Giorgio; Spyrakis, Francesca; Franzoni, Lorella; Galdeano, Carles; Bidon-Chanal, Axel; Luigi Gervasio, Francesco; Javier Luque, F.. - In: THE JOURNAL OF PHYSICAL CHEMISTRY LETTERS. - ISSN 1948-7185. - 10:23(2019), pp. 7333-7339. [10.1021/acs.jpclett.9b02861]

Modulating Ligand Dissociation through Methyl Isomerism in Accessory Sites: Binding of Retinol to Cellular Carriers

Francesca Spyrakis;Lorella Franzoni;
2019

Abstract

Due to the poor aqueous solubility of retinoids, evolution has tuned their binding to cellular proteins to address specialized physiological roles by modulating uptake, storage, and delivery to specific targets. With the aim to disentangle the structure-function relationships in these proteins and disclose clues for engineering selective carriers, the binding mechanism of the two most abundant retinol-binding isoforms was explored by using enhanced sampling molecular dynamics simulations and surface plasmon resonance. The distinctive dynamics of the entry portal site in the holo species was crucial to modulate retinol dissociation. Remarkably, this process is controlled to a large extent by the replacement of Ile by Leu in the two isoforms, thus suggesting that fine control of ligand release can be achieved through a rigorous selection of conservative mutations in accessory sites.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11381/2879546
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