Analysis of Catalytic Residues in Enzyme Active Sites

Bartlett, Gail J.; Porter, Craig T.; Borkakoti, Neera; Thornton, Janet M.

doi:10.1016/s0022-2836(02)01036-7

Cited by 537 publications

(577 citation statements)

References 42 publications

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“…An obvious solution to this apparent contradiction is to restrict induced fit motions to surface loops which can close over the catalytic machinery located at the base of the active site. There is a suggestion of this in the results obtained by Bartlett et al [8] which showed that catalytic residues generally have small solvent exposure and so do not lie on surface exposed loops.…”

Section: Discussionmentioning

confidence: 93%

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Conformational change in substrate binding, catalysis and product release: an open and shut case?

GUTTERIDGE¹

2004

FEBS Letters

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The role of conformational change in substrate binding, catalysis and product release is reviewed for 11 enzymes, for which crystal structures are available for the apo, substrateand product-bound states. The extent of global conformational changes is measured, and the movements of the functional regions involved in catalysis and ligand binding are compared to the rest of the structure. We find that most of these enzymes undergo relatively small amounts of conformational change and particularly small changes in catalytic residue geometry, usually less than 1 A. In some enzymes there is significant movement of the binding residues, usually on surface loops.

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Section: Discussionmentioning

confidence: 93%

“…The binding residues are defined as any residue with any atom within 4 A of a bound substrate. The catalytic residues are extracted from the literature following the definition of catalytic used by Bartlett et al [8]. A residue is defined as catalytic if any of the following are true: 1.…”

Section: Review Of Enzyme Structuresmentioning

confidence: 99%

Conformational change in substrate binding, catalysis and product release: an open and shut case?

GUTTERIDGE¹

2004

FEBS Letters

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“…Identification of catalytic residues is an important step to know the function of enzymes [70]. The binding site regions and the active site residues were identified using CASTp, Q-site Finder and SiteMap tools; the results of which are shown in the Tables 3 and 4.…”

Section: Active Site Predictionmentioning

confidence: 99%

Targeting the ubiquitin-conjugating enzyme E2D4 for cancer drug discovery–a structure-based approach

et al. 2016

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Cancer progression is a global burden. The incidence and mortality now reach 30 million deaths per year. Several pathways of cancer are under investigation for the discovery of effective therapeutics. The present study highlights the structural details of the ubiquitin protein 'Ubiquitin-conjugating enzyme E2D4' (UBE2D4) for the novel lead structure identification in cancer drug discovery process. The evaluation of 3D structure of UBE2D4 was carried out using homology modelling techniques. The optimized structure was validated by standard computational protocols. The active site region of the UBE2D4 was identified using computational tools like CASTp, Q-site Finder and SiteMap. The hydrophobic pocket which is responsible for binding with its natural receptor ubiquitin ligase CHIP (C-terminal of Hsp 70 interacting protein) was identified through proteinprotein docking study. Corroborating the results obtained from active site prediction tools and protein-protein docking study, the domain of UBE2D4 which is responsible for cancer cell progression is sorted out for further docking study. Virtual screening with large structural database like CB_Div Set and Asinex BioDesign small molecular structural database was carried out. The obtained new ligand molecules that have shown affinity towards UBE2D4 were considered for ADME prediction studies. The identified new ligand molecules with acceptable parameters of docking, ADME are considered as potent UBE2D4 enzyme inhibitors for cancer therapy.

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“…Furthermore, many structural characteristics related to identification of critical residues have been intensively investigated, such as the secondary structure information etc. [28-34]. David et al [7] has made a comprehensive characterization of protein interaction interfaces, and found that main-chain atoms contribute significantly to protein-protein interactions, where the type of interaction is highly dependent on the secondary structure type.…”

Section: Introductionmentioning

confidence: 99%

Predicting protein-ATP binding sites from primary sequence through fusing bi-profile sampling of multi-view features

Zhang

et al. 2012

BMC Bioinformatics

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BackgroundAdenosine-5′-triphosphate (ATP) is one of multifunctional nucleotides and plays an important role in cell biology as a coenzyme interacting with proteins. Revealing the binding sites between protein and ATP is significantly important to understand the functionality of the proteins and the mechanisms of protein-ATP complex.ResultsIn this paper, we propose a novel framework for predicting the proteins’ functional residues, through which they can bind with ATP molecules. The new prediction protocol is achieved by combination of sequence evolutional information and bi-profile sampling of multi-view sequential features and the sequence derived structural features. The hypothesis for this strategy is single-view feature can only represent partial target’s knowledge and multiple sources of descriptors can be complementary.ConclusionsPrediction performances evaluated by both 5-fold and leave-one-out jackknife cross-validation tests on two benchmark datasets consisting of 168 and 227 non-homologous ATP binding proteins respectively demonstrate the efficacy of the proposed protocol. Our experimental results also reveal that the residue structural characteristics of real protein-ATP binding sites are significant different from those normal ones, for example the binding residues do not show high solvent accessibility propensities, and the bindings prefer to occur at the conjoint points between different secondary structure segments. Furthermore, results also show that performance is affected by the imbalanced training datasets by testing multiple ratios between positive and negative samples in the experiments. Increasing the dataset scale is also demonstrated useful for improving the prediction performances.

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Analysis of Catalytic Residues in Enzyme Active Sites

Cited by 537 publications

References 42 publications

Conformational change in substrate binding, catalysis and product release: an open and shut case?

Conformational change in substrate binding, catalysis and product release: an open and shut case?

Targeting the ubiquitin-conjugating enzyme E2D4 for cancer drug discovery–a structure-based approach

Predicting protein-ATP binding sites from primary sequence through fusing bi-profile sampling of multi-view features

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