Strain energy in enzyme–substrate binding: An energetic insight into the flexibility versus rigidity of enzyme active site

Guo, Xinchun; He, Deyong; Huang, Lanqing; Liu, Limin; Liu, Lijun; Yang, Huijuan

doi:10.1016/j.comptc.2012.06.017

Cited by 28 publications

(13 citation statements)

References 48 publications

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“…This is usually interpreted as the blueprint of an optimal structural compactness at the active site, where reaction partners are kept tight in the optimal geometry that underlies the catalytically competent atomic arrangement. This fact perfectly rhymes with the known reports that active sites tend to lie in the stiffest regions of enzyme structures 35–37 and that a subtle balance of rigidity and some specific flexibility are implied in enzyme catalysis 38,39 .…”

Section: Introductionsupporting

confidence: 87%

Universality of fold-encoded localized vibrations in enzymes

Chalopin

Piazza

Mayboroda

et al. 2019

Sci Rep

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Enzymes speed up biochemical reactions at the core of life by as much as 15 orders of magnitude. Yet, despite considerable advances, the fine dynamical determinants at the microscopic level of their catalytic proficiency are still elusive. In this work, we use a powerful mathematical approach to show that rate-promoting vibrations in the picosecond range, specifically encoded in the 3D protein structure, are localized vibrations optimally coupled to the chemical reaction coordinates at the active site. Remarkably, our theory also exposes an hithertho unknown deep connection between the unique localization fingerprint and a distinct partition of the 3D fold into independent, foldspanning subdomains that govern long-range communication. The universality of these features is demonstrated on a pool of more than 900 enzyme structures, comprising a total of more than 10,000 experimentally annotated catalytic sites. Our theory provides a unified microscopic rationale for the subtle structure-dynamics-function link in proteins.

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Section: Introductionsupporting

confidence: 87%

Universality of fold-encoded localized vibrations in enzymes

Chalopin

Piazza

Mayboroda

et al. 2019

Sci Rep

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“…Here, the strain energy was calculated to range from 8.7 to 21.8 kcal/mol, which is larger than those of strain energies involved in routine enzyme–ligand interactions (<10 kcal/mol). [ 21 ] Although the strain energy is not very high as compared to those accounted for solvent effect and, more significantly, noncovalent interaction, it should not be ignored if considering that the total binding energy of EGFR–inhibitor complex systems is just about −9 kcal/mol, which is at the same level of the strain energy. Interestingly, it is evident from Figure 3a that the curves of solvent effect and interaction energy exhibit a complementary profile over the 11 inhibitor samples, that is, the stronger the interaction energy is, the more the solvent penalty should be paid, and vice versa.…”

Section: Resultsmentioning

confidence: 99%

Molecular analysis and systematic profiling of allosteric inhibitor response to clinically significant epidermal growth factor receptor missense mutations in non‐small cell lung cancer

Zhao

Zhu

Gao

2021

J Chinese Chemical Soc

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Human epidermal growth factor receptor (EGFR) is an attractive anti-non-small cell lung cancer (anti-NSCLC) druggable target, but many traditional adenosine triphosphate (ATP)-competitive EGFR inhibitors have been clinically observed to eventually establish acquired resistance due to kinase mutations. Allosteric inhibitors represent a new direction of EGFR-targeted therapy, which have been successfully developed since 2016 to overcome the widely occurring kinase drug-resistant mutations T790M/C797S [Jia Y, et al. Nature 2016; 534: 129-132].In this study, a systematic inhibitor response-to-mutation profile of 11 reported EGFR allosteric inhibitors against 17 clinically significant EGFR missense muta-

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“…It was previously assumed that substrate specificity of an enzyme is determined by stereo-chemical complementarities with its active site [ 36 - 39 ]; however, these preferences are not stringent enough. It has since been found that, in addition to substrate target site preferences, many protein kinases uses dedicated modular protein-protein interaction docking domains, interactions involving binding of the surface of the catalytic domain, but distinct from catalytic active sites [ 40 - 42 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of new members of the MAPK gene family in plants shows diverse conserved domains and novel activation loop variants

et al. 2015

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BackgroundMitogen Activated Protein Kinase (MAPK) signaling is of critical importance in plants and other eukaryotic organisms. The MAPK cascade plays an indispensible role in the growth and development of plants, as well as in biotic and abiotic stress responses. The MAPKs are constitute the most downstream module of the three tier MAPK cascade and are phosphorylated by upstream MAP kinase kinases (MAPKK), which are in turn are phosphorylated by MAP kinase kinase kinase (MAPKKK). The MAPKs play pivotal roles in regulation of many cytoplasmic and nuclear substrates, thus regulating several biological processes.ResultsA total of 589 MAPKs genes were identified from the genome wide analysis of 40 species. The sequence analysis has revealed the presence of several N- and C-terminal conserved domains. The MAPKs were previously believed to be characterized by the presence of TEY/TDY activation loop motifs. The present study showed that, in addition to presence of activation loop TEY/TDY motifs, MAPKs are also contain MEY, TEM, TQM, TRM, TVY, TSY, TEC and TQY activation loop motifs. Phylogenetic analysis of all predicted MAPKs were clustered into six different groups (group A, B, C, D, E and F), and all predicted MAPKs were assigned with specific names based on their orthology based evolutionary relationships with Arabidopsis or Oryza MAPKs.ConclusionWe conducted global analysis of the MAPK gene family of plants from lower eukaryotes to higher eukaryotes and analyzed their genomic and evolutionary aspects. Our study showed the presence of several new activation loop motifs and diverse conserved domains in MAPKs. Advance study of newly identified activation loop motifs can provide further information regarding the downstream signaling cascade activated in response to a wide array of stress conditions, as well as plant growth and development.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1244-7) contains supplementary material, which is available to authorized users.

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Strain energy in enzyme–substrate binding: An energetic insight into the flexibility versus rigidity of enzyme active site

Cited by 28 publications

References 48 publications

Universality of fold-encoded localized vibrations in enzymes

Universality of fold-encoded localized vibrations in enzymes

Molecular analysis and systematic profiling of allosteric inhibitor response to clinically significant epidermal growth factor receptor missense mutations in non‐small cell lung cancer

Identification of new members of the MAPK gene family in plants shows diverse conserved domains and novel activation loop variants

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