Exploring and exploiting allostery: Models, evolution, and drug targeting

Peracchi, Alessio; Mozzarelli, Andrea

doi:10.1016/j.bbapap.2010.10.008

Cited by 69 publications

(56 citation statements)

References 147 publications

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“…Allostery is envisioned to have evolved by oligomerization, gene fusion and/or recruitment of unused/flexible parts of a pre-existing protein structure (reviewed in [199]). The latter evolutionary route may proceed by positive selection of opportunistic binding of excited-state conformations.…”

Section: Conformational Diversity Is Often Needed For Functionmentioning

confidence: 99%

Biophysics of protein evolution and evolutionary protein biophysics

Sikosek

Chan

2014

J. R. Soc. Interface.

224

207

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The study of molecular evolution at the level of protein-coding genes often entails comparing large datasets of sequences to infer their evolutionary relationships. Despite the importance of a protein's structure and conformational dynamics to its function and thus its fitness, common phylogenetic methods embody minimal biophysical knowledge of proteins. To underscore the biophysical constraints on natural selection, we survey effects of protein mutations, highlighting the physical basis for marginal stability of natural globular proteins and how requirement for kinetic stability and avoidance of misfolding and misinteractions might have affected protein evolution. The biophysical underpinnings of these effects have been addressed by models with an explicit coarse-grained spatial representation of the polypeptide chain. Sequence-structure mappings based on such models are powerful conceptual tools that rationalize mutational robustness, evolvability, epistasis, promiscuous function performed by 'hidden' conformational states, resolution of adaptive conflicts and conformational switches in the evolution from one protein fold to another. Recently, protein biophysics has been applied to derive more accurate evolutionary accounts of sequence data. Methods have also been developed to exploit sequence-based evolutionary information to predict biophysical behaviours of proteins. The success of these approaches demonstrates a deep synergy between the fields of protein biophysics and protein evolution.

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Section: Conformational Diversity Is Often Needed For Functionmentioning

confidence: 99%

Biophysics of protein evolution and evolutionary protein biophysics

Sikosek

Chan

2014

J. R. Soc. Interface.

224

207

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“…Allostery is indeed an example of gratuity [40]. The evolutionary origin of allostery [49] supports the bona fide nature of this code, allowing the implementation of information transfer along the genome. We suggest that the histone code would be better termed a context-dependent transcription regulatory code [54], translated by the chromatin fiber allosteric transitions.…”

Section: Chromatin Fiber Allostery May Be Involved In the Translationmentioning

confidence: 99%

“…Quoting [41]: "The absence of any inherent obligatory chemical analogy or reactivity between substrate and allosteric effector appears to be a fact of extreme biological importance." This gratuity is related to the evolutionary origin of allostery , which has been experimentally demonstrated for proteins by means of phylogenetic analyses or directed evolution experiments [49]. The involvement of natural selection in the design of allosteric entities and mechanisms was already underlined in [41]: " The specific structure of any enzyme-protein is of course a pure product of selection, necessarily limited, however, by the structure and chemical properties of the actual reactants."…”

Section: A Biological Code Relies On a Co-evolved Adaptormentioning

confidence: 99%

Chromatin fiber allostery and the epigenetic code

Lesne

Foray

Cathala

et al. 2015

J. Phys.: Condens. Matter

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Abstract. The notion of allostery introduced for proteins about fifty years ago has been extended since then to DNA allostery, where a locally triggered DNA structural transition remotely controls other DNA-binding events. We further extend this notion and propose that chromatin fiber allosteric transitions, induced by histone-tail covalent modifications, may play a key role in transcriptional regulation. We present an integrated scenario articulating allosteric mechanisms at different scales: allosteric transitions of the condensed chromatin fiber induced by histone-tail acetylation modify the mechanical constraints experienced by the embedded DNA, thus possibly controlling DNA-binding of allosteric transcription factors or further allosteric mechanisms at the linker DNA level. At a higher scale, different epigenetic constraints delineate different statistically dominant subsets of accessible chromatin fiber conformations, which each favors the assembly of dedicated regulatory complexes, as detailed on the emblematic example of the mouse Igf2-H19 gene locus and its parental imprinting. This physical view offers a mechanistic and spatially structured explanation of the observed correlation between transcriptional activity and histone modifications. The evolutionary origin of allosteric control supports to speak of an "epigenetic code", by which events involved in transcriptional regulation are encoded in histone modifications in a context-dependent way.

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“…A conformational change induced by ligand binding may influence structural and binding properties of remote sites for the same or a structurally unrelated ligand. [26][27][28][29][30] The binding event could reduce or enhance protein motions affecting only the entropy of the system, enabling allosteric effects to be based solely on protein rigidity. 10 Also, the dynamic properties of the active site could have significant influence on the rate of the catalytic step.…”

Section: Discussionmentioning

confidence: 99%

Influence of Subunit Interface Mutations on Kinetic and Dynamic Properties of Alkaline Phosphatase from E. coli

Šprung¹,

Bučević-Popović²,

Soldo³

et al. 2013

Croat. Chem. Acta

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Abstract. Mutations, replacing amino acids involved in the formation of hydrogen bonds between subunits of dimeric alkaline phosphatase, have been introduced. Influence of mutations on kinetic properties and structural stability of mutant enzymes was established. In addition, alterations in protein dynamic properties have been studied using room temperature phosphorescence. Kinetic properties of both mutant enzymes were virtually the same, differing from the wild type enzyme in the k cat value that was almost twice lower. Changes in protein dynamic properties of mutant proteins, compared to the wild type enzyme, did not parallel changes in kinetic properties suggesting that an alteration in the rigidity of the Trp109 environment is not responsible for the reduction of kinetic properties. Instead, combined kinetic and dynamic consequences of introduced mutations suggest that breaking of specific links, involved in transmission of conformational change, could be responsible for altered kinetic properties. (doi: 10.5562/cca2168)

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Exploring and exploiting allostery: Models, evolution, and drug targeting

Cited by 69 publications

References 147 publications

Biophysics of protein evolution and evolutionary protein biophysics

Biophysics of protein evolution and evolutionary protein biophysics

Chromatin fiber allostery and the epigenetic code

Influence of Subunit Interface Mutations on Kinetic and Dynamic Properties of Alkaline Phosphatase from E. coli

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