GapRepairer: a server to model a structural gap and validate it using topological analysis

Jarmolinska, Aleksandra I.; Kadlof, Michal; Dąbrowski-Tumański, Paweł; Sułkowska, Joanna I.

doi:10.1093/bioinformatics/bty334

Cited by 13 publications

(7 citation statements)

References 31 publications

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“…We chose only one chain from each protein and identified 13,320 covalent loops in a total. This dataset includes 1276 chains with unresolved parts which were reconstructed with Gaprepair 42 based on Modeller 43 . For details see Supplementary Information file.…”

Section: Methodsmentioning

confidence: 99%

GLN: a method to reveal unique properties of lasso type topology in proteins

Niemyska

Millett

Sułkowska

2020

Sci Rep

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Geometry and topology are the main factors that determine the functional properties of proteins. In this work, we show how to use the Gauss linking integral (GLN) in the form of a matrix diagram—for a pair of a loop and a tail—to study both the geometry and topology of proteins with closed loops e.g. lassos. We show that the GLN method is a significantly faster technique to detect entanglement in lasso proteins in comparison with other methods. Based on the GLN technique, we conduct comprehensive analysis of all proteins deposited in the PDB and compare it to the statistical properties of the polymers. We show how high and low GLN values correlate with the internal exibility of proteins, and how the GLN in the form of a matrix diagram can be used to study folding and unfolding routes. Finally, we discuss how the GLN method can be applied to study entanglement between two structures none of which are closed loops. Since this approach is much faster than other linking invariants, the next step will be evaluation of lassos in much longer molecules such as RNA or loops in a single chromosome.

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Section: Methodsmentioning

confidence: 99%

GLN: a method to reveal unique properties of lasso type topology in proteins

Niemyska

Millett

Sułkowska

2020

Sci Rep

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“…The structures of CK1ε apo (PDB ID 4HOK), alone and cocrystallized with IN1 (PDB ID 4HNI) [22], were obtained from the RCSB Protein Data Bank. The unresolved fragments of the structures were built by homology modeling using the GapRepairer server [42].…”

Section: Protein Preparationmentioning

confidence: 99%

Repositioning of Etravirine as a Potential CK1ε Inhibitor by Virtual Screening

et al. 2021

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CK1ε is a key regulator of WNT/β-catenin and other pathways that are linked to tumor progression; thus, CK1ε is considered a target for the development of antineoplastic therapies. In this study, we performed a virtual screening to search for potential CK1ε inhibitors. First, we characterized the dynamic noncovalent interactions profiles for a set of reported CK1ε inhibitors to generate a pharmacophore model, which was used to identify new potential inhibitors among FDA-approved drugs. We found that etravirine and abacavir, two drugs that are approved for HIV infections, can be repurposed as CK1ε inhibitors. The interaction of these drugs with CK1ε was further examined by molecular docking and molecular dynamics. Etravirine and abacavir formed stable complexes with the target, emulating the binding behavior of known inhibitors. However, only etravirine showed high theoretical binding affinity to CK1ε. Our findings provide a new pharmacophore for targeting CK1ε and implicate etravirine as a CK1ε inhibitor and antineoplastic agent.

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“…We chose only one chain from each protein and identified 13,320 covalent loops in a total. This dataset includes 1,276 chains with unresolved parts which were reconstructed with Gaprepair [43] based on Modeller [44]. For details see Supplementary Information file.…”

Section: Let Us Denotementioning

confidence: 99%

GLN -- a method to reveal unique properties of lasso type topology in proteins

Niemyska¹,

Millett²,

Sułkowska³

2020

Preprint

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Geometry and topology are the main factors that determine the functional properties of proteins. In this work, we show how to use the Gauss linking integral (GLN) in the form of a matrix diagramfor a pair of a loop and a tail -to study both the geometry and topology of proteins with closed loops e.g. lassos. We show that the GLN method is a significantly faster technique to detect entanglement in lasso proteins in comparison with other methods. Based on the GLN technique, we conduct comprehensive analysis of all proteins deposited in the PDB and compare it to the statistical properties of the polymers. We found that there are significantly more lassos with negative crossings than those with positive ones in proteins, the average value of maxGLN (maximal GLN between loop and pieces of tail) depends logarithmically on the length of a tail similarly as in the polymers. Next, we show the how high and low GLN values correlate with the internal flexibility of proteins, and how the GLN in the form of a matrix diagram can be used to study folding and unfolding routes. Finally, we discuss how the GLN method can be applied to study entanglement between two structures none of which are closed loops. Since this approach is much faster than other linking invariants, the next step will be evaluation of lassos in much longer molecules such as RNA or loops in a single chromosome.

show abstract

GapRepairer: a server to model a structural gap and validate it using topological analysis

Abstract: Supplementary data are available at Bioinformatics online.

Cited by 13 publications

References 31 publications

GLN: a method to reveal unique properties of lasso type topology in proteins

GLN: a method to reveal unique properties of lasso type topology in proteins

Repositioning of Etravirine as a Potential CK1ε Inhibitor by Virtual Screening

GLN -- a method to reveal unique properties of lasso type topology in proteins

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