A two-quartet G-quadruplex topology of human KIT2 is conformationally selected by a perylene derivative

Autor: Claudia Sissi, Eric Largy, Silvia Ceschi, Valérie Gabelica
Přispěvatelé: Acides Nucléiques : Régulations Naturelle et Artificielle (ARNA), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), CCSD, Accord Elsevier, Università degli Studi di Padova = University of Padua (Unipd)
Rok vydání: 2020
Předmět:
0301 basic medicine
Circular dichroism
Electrophoretic Mobility Shift Assay
Ligands
Biochemistry
chemistry.chemical_compound
Piperidines
Side chain
Promoter Regions
Genetic
[SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry
Molecular Biology/Biochemistry [q-bio.BM]
Perylene
ComputingMilieux_MISCELLANEOUS
[PHYS.PHYS.PHYS-BIO-PH] Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph]
[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Structural Biology [q-bio.BM]
Circular Dichroism
General Medicine
[CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry
[SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Biophysics
Proto-Oncogene Proteins c-kit
Thermodynamics
Spectrometry
Mass
Electrospray Ionization
[CHIM.ANAL] Chemical Sciences/Analytical chemistry
[SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry
Molecular Biology/Structural Biology [q-bio.BM]
[PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph]
Electrospray ionization
Stacking
[SDV.BBM.BP] Life Sciences [q-bio]/Biochemistry
Molecular Biology/Biophysics
c-KIT
G-quadruplex folding
Native ESI-MS
G-quadruplex
Topology
Antiparallel (biochemistry)
[PHYS.PHYS.PHYS-CHEM-PH] Physics [physics]/Physics [physics]/Chemical Physics [physics.chem-ph]
03 medical and health sciences
[CHIM.ANAL]Chemical Sciences/Analytical chemistry
Cations
Humans
[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Biochemistry [q-bio.BM]
030102 biochemistry & molecular biology
Ligand
DNA
G-Quadruplexes
[CHIM.THEO] Chemical Sciences/Theoretical and/or physical chemistry
030104 developmental biology
chemistry
Potassium
[PHYS.PHYS.PHYS-CHEM-PH]Physics [physics]/Physics [physics]/Chemical Physics [physics.chem-ph]
Zdroj: Biochimie
Biochimie, Elsevier, 2020, 179, pp.77-84. ⟨10.1016/j.biochi.2020.09.015⟩
Biochimie, 2020, 179, pp.77-84. ⟨10.1016/j.biochi.2020.09.015⟩
ISSN: 1638-6183
0300-9084
DOI: 10.1016/j.biochi.2020.09.015⟩
Popis: International audience; G-quadruplexes are promising targets for innovative anticancer therapy. Hence, many efforts are being made to find selective ligands. Drug design is often based on the available high-resolution structures, obtained for the thermodynamically stable forms. However, the complexity of the G-quadruplex folding landscape has clearly emerged in recent years, with the discovery of intermediate conformations that persist on the second to the minute time scale. In the case of the KIT2 G-quadruplex forming sequence, found within human c-KIT promoter, we recently identified a long-lived folding intermediate, characterized by guanine stacking in alternating orientation (as determined by circular dichroism). Given the rate of transcriptional processes, a physiological role of this arrangement should not be excluded. In the present study, we applied circular dichroism (CD) spectroscopy, native electrospray ionization mass spectrometry (ESI-MS) and electrophoretic mobility shift assays (EMSA) to show that a perylene derivative (K20) selects this topology. Interestingly, ESI-MS spectra revealed the presence of a single specifically coordinated K+ ion in the structure, which is thus presumably composed of only two consecutive G-quartets. The parent ligand PIPER failed to promote the same conformational selection, which is therefore a process strictly dependent on the perylene side chains composition. The greater affinity of K20 for the two-quartet antiparallel topology, compared to PIPER, was finally corroborated by evaluating their binding to the KIT∗ G-quadruplex, which is also found within the human promoter of c-KIT.
Databáze: OpenAIRE
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