Abstract
The structure of ligand-binding sites has been shown to profoundly influence the evolution of function in homomeric protein complexes. Complexes with multichain binding sites (MBSs) have more conserved quaternary structure, more similar binding sites and ligands between homologs, and evolve new functions slower than homomers with single-chain binding sites (SBSs). Here, using in silico analyses of protein dynamics, we investigate whether ligand-binding-site structure shapes allosteric signal transduction pathways, and whether the structural similarity of binding sites influences the evolution of allostery. Our analyses show that: 1) allostery is more frequent among MBS complexes than in SBS complexes, particularly in homomers; 2) in MBS homomers, semirigid communities and critical residues frequently connect interfaces and thus they are characterized by signal transduction pathways that cross protein–protein interfaces, whereas SBS homomers usually not; 3) ligand binding alters community structure differently in MBS and SBS homomers; and 4) except MBS homomers, allosteric proteins are more likely to have homologs with similar binding site than nonallosteric proteins, suggesting that binding site similarity is an important factor driving the evolution of allostery.
Highlights
IntroductionUsually experience conformational changes upon binding their ligands(Pabis et al 2018)
Proteins are dynamic entities, and usually experience conformational changes upon binding their ligands(Pabis et al 2018)
We address the following questions: 1) Are MBS complexes more likely to be allosteric than SBS complexes? 2) Are there qualitative differences in the topology and functioning of allosteric pathways in MBS and SBS complexes? 3) Does the structural similarity of binding sites influence the frequency of allostery?
Summary
Usually experience conformational changes upon binding their ligands(Pabis et al 2018). Allostery is a special case of conformational change induced by ligand binding, which is characterized by information transfer within proteins Allosteric ligands can be activators, inhibitors or regulators, depending on their effect on the orthosteric site, and are usually required for the normal functioning – or inhibition of function – of allosteric proteins. Allostery has large practical importance for drug design, because allosteric sites are druggable, and in the case of proteins with structurally similar orthosteric sites (for example in protein kinases, with similar ATP binding sites (Kornev and Taylor 2015; Dokholyan 2016)), drugs that bind allosteric sites allow targeting specific proteins, without the side effects of molecules that bind their unspecific orthosteric site
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