A Single Mutation in a Tunnel to the Active Site Changes the Mechanism and Kinetics of Product Release in Haloalkane Dehalogenase LinB

Biedermannová, Lada; Prokop, Zbyněk; Góra, Artur; Chovancová, Eva; Kovács, Mihály; Damborský, Jiřı́; Wade, Rebecca C.

doi:10.1074/jbc.m112.377853

Cited by 62 publications

(78 citation statements)

References 54 publications

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“…For example, internal pores of ion channels maintain a highly selective ionic balance between the cell interior and exterior, [2-6] photosystem II channels are involved in photosynthesis, [7,8] ribosomal polypeptide exit channels allow nascent peptides to leave the ribosome during translation, [9] and active site access/egress channels enable substrate/product to enter/leave the occluded active sites of various enzymes (e.g., cytochrome P450, [10-15] acetylcholinesterase, [16-18] etc.). Information about the nature of active site access paths can also be utilized in biotechnology applications aimed at designing more effective and selective enzymes [19-21]. Unquestionably, identification and characterization of channels are fundamental to understanding numerous biologically relevant processes and serve as a starting point for rational drug design, protein engineering and biotechnological applications.…”

Section: Introductionmentioning

confidence: 99%

MOLE 2.0: advanced approach for analysis of biomacromolecular channels

et al. 2013

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BackgroundChannels and pores in biomacromolecules (proteins, nucleic acids and their complexes) play significant biological roles, e.g., in molecular recognition and enzyme substrate specificity.ResultsWe present an advanced software tool entitled MOLE 2.0, which has been designed to analyze molecular channels and pores. Benchmark tests against other available software tools showed that MOLE 2.0 is by comparison quicker, more robust and more versatile. As a new feature, MOLE 2.0 estimates physicochemical properties of the identified channels, i.e., hydropathy, hydrophobicity, polarity, charge, and mutability. We also assessed the variability in physicochemical properties of eighty X-ray structures of two members of the cytochrome P450 superfamily.ConclusionEstimated physicochemical properties of the identified channels in the selected biomacromolecules corresponded well with the known functions of the respective channels. Thus, the predicted physicochemical properties may provide useful information about the potential functions of identified channels. The MOLE 2.0 software is available at http://mole.chemi.muni.cz.

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Section: Introductionmentioning

confidence: 99%

MOLE 2.0: advanced approach for analysis of biomacromolecular channels

et al. 2013

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“…When conformers of rigid proteins are compared, for example in their bound and unbound states, we find that they mainly differ in backbone positions associated with their tunnels and cavities. This indicates that the minimum movements for rigid proteins are associated with the movement of functional structures to allow the transit of substrates and/or products between the inside and the surface of the protein [64][65][66]. It is for this group of proteins that sequence-structure relationships show a high correlation between variables, and for whom it would be possible to reliably predict 3D models using TMB techniques (see Fig 5a).…”

Section: Discussionmentioning

confidence: 99%

Homology modeling in a dynamical world

Monzón

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Marino-Buslje

et al. 2017

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A key concept in template-based modeling is the high correlation between sequence and structural divergence, with the practical consequence that homologous proteins that are similar at the sequence level will also be similar at the structural level. However, conformational diversity of the native state will reduce the correlation between structural and sequence divergence, because structural variation can appear without sequence diversity.In this work, we explore the impact that conformational diversity has on the relationship between structural and sequence divergence. We find that the extent of conformational diversity can be as high as the maximum structural divergence among families. Also, as expected, conformational diversity impairs the well-established correlation between sequence and structural divergence, which is nosier than previously suggested. However, we found that this noise can be resolved using a priori information coming from the structure-function relationship.We show that protein families with low conformational diversity show a well-correlated relationship between sequence and structural divergence, which is severely reduced in proteins with larger conformational diversity. This lack of correlation could impair Template-based modelling (TMB) results in highly dynamical proteins. Finally, we also find that the presence of order/disorder can provide useful beforehand information for better TBM performance. Author summaryTemplate-based modelling (TBM) is the most reliable and fastest approach to obtain protein structural models. TBM relies in the high correlation between sequence and structural divergence, with the practical consequence that proteins that are similar at the sequence level will also be similar at the structural level, allowing in this way the selection of the better template to obtain the 3D model of the target sequence. However, protein native state could be described by a collection of conformers in equilibrium where their structural differences are called conformational diversity.In this work, we explore the impact that conformational diversity has on the relationship between structural and sequence divergence. We firstly found that the extent of conformational diversity can be as high as the maximum structural differences reached by families differing in their sequences. In these proteins with higher conformational diversity levels, the well-established correlation between sequence and structural divergence is nosier than previously suggested . CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/135004 doi: bioRxiv preprint first posted online May. 6, 2017; 3 due to the presence of structural change without sequence variation. This lack of correlation could impair TBM results due to the uncertainty in the correct template selection. Finally, we also found that the presence of order/disorder can provide useful beforehand information ...

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“…When conformers of rigid proteins are compared, for example, in their bound and unbound states, we find that they mainly differ in backbone positions associated with their tunnels and cavities. This indicates that the minimum movements for rigid proteins are associated with the movement of functional structures to allow the transit of substrates and/or products between the inside and the surface of the protein . It is for this group of proteins that sequence‐structure relationships show a high correlation between variables, and for whom it would be possible to reliably predict 3D models using TMB techniques [see Fig.…”

Section: Discussionmentioning

confidence: 99%

“…This indicates that the minimum movements for rigid proteins are associated with the movement of functional structures to allow the transit of substrates and/or products between the inside and the surface of the protein. [67][68][69] It is for this group of proteins that sequence-structure relationships show a high correlation between variables, and for whom it would be possible to reliably predict 3D models using TMB techniques [see Fig. 5(A)].…”

Section: Discussionmentioning

confidence: 99%

Homology modeling in a dynamical world

et al. 2017

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A key concept in template-based modeling (TBM) is the high correlation between sequence and structural divergence, with the practical consequence that homologous proteins that are similar at the sequence level will also be similar at the structural level. However, conformational diversity of the native state will reduce the correlation between structural and sequence divergence, because structural variation can appear without sequence diversity. In this work, we explore the impact that conformational diversity has on the relationship between structural and sequence divergence. We find that the extent of conformational diversity can be as high as the maximum structural divergence among families. Also, as expected, conformational diversity impairs the well-established correlation between sequence and structural divergence, which is nosier than previously suggested. However, we found that this noise can be resolved using a priori information coming from the structure-function relationship. We show that protein families with low conformational diversity show a well-correlated relationship between sequence and structural divergence, which is severely reduced in proteins with larger conformational diversity. This lack of correlation could impair TBM results in highly dynamical proteins. Finally, we also find that the presence of order/disorder can provide useful beforehand information for better TBM performance.

show abstract

A Single Mutation in a Tunnel to the Active Site Changes the Mechanism and Kinetics of Product Release in Haloalkane Dehalogenase LinB

Cited by 62 publications

References 54 publications

MOLE 2.0: advanced approach for analysis of biomacromolecular channels

MOLE 2.0: advanced approach for analysis of biomacromolecular channels

Homology modeling in a dynamical world

Homology modeling in a dynamical world

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