Page last updated: 2024-10-24

G-quadruplex DNA binding

Definition

Target type: molecularfunction

Binding to G-quadruplex DNA structures, in which groups of four guanines adopt a flat, cyclic Hoogsteen hydrogen-bonding arrangement known as a guanine tetrad. The stacking of guanine tetrads results in G-quadruplex DNA structures. G-quadruplex DNA can form under physiological conditions from some G-rich sequences, such as those found in telomeres, immunoglobulin switch regions, gene promoters, fragile X repeats, and the dimerization domain in the human immunodeficiency virus (HIV) genome. [PMID:16142245, PMID:9512530]

G-quadruplex DNA binding refers to the interaction of proteins or small molecules with G-quadruplex structures within DNA. G-quadruplexes are non-canonical DNA structures formed by guanine-rich sequences, characterized by stacked planar G-quartets, where four guanines are linked by Hoogsteen hydrogen bonds. These structures can adopt various topologies, including parallel, antiparallel, and hybrid forms, and are implicated in diverse cellular functions.

The molecular function of G-quadruplex DNA binding involves recognition and interaction of the binding entity with the G-quadruplex structure. This interaction can be driven by various factors, including:

* **Shape complementarity:** The binding entity may possess a shape that fits into the grooves or loops of the G-quadruplex, promoting specific binding.
* **Electrostatic interactions:** Positive charges on the binding entity can interact with the negatively charged phosphate backbone of the G-quadruplex.
* **Hydrogen bonding:** Specific amino acid residues or functional groups on the binding entity can form hydrogen bonds with the guanine bases within the G-quadruplex.
* **Hydrophobic interactions:** Non-polar residues on the binding entity can interact with the hydrophobic core of the G-quadruplex.
* **Stacking interactions:** Aromatic rings on the binding entity can stack onto the G-quartets within the G-quadruplex, contributing to stabilization.

These interactions can influence the stability, conformation, and function of the G-quadruplex, potentially regulating gene expression, telomere maintenance, and other cellular processes. For example, G-quadruplex binding proteins can modulate DNA replication, transcription, and translation by stabilizing or destabilizing G-quadruplex structures.

G-quadruplex DNA binding has significant implications in drug discovery and development. Small molecules that bind to G-quadruplexes have been investigated as potential therapeutics for various diseases, including cancer, neurodegenerative disorders, and infectious diseases. These molecules can target specific G-quadruplex structures involved in disease pathogenesis and exert therapeutic effects by modulating gene expression, inhibiting enzyme activity, or disrupting DNA replication.'
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Proteins (4)

ProteinDefinitionTaxonomy
Werner syndrome ATP-dependent helicaseA bifunctional 3-5 exonuclease/ATP-dependent helicase WRN that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q14191]Homo sapiens (human)
Bloom syndrome proteinA RecQ-like DNA helicase BLM that is encoded in the genome of human. [PRO:DNx, UniProtKB:P54132]Homo sapiens (human)
Lon protease homolog, mitochondrialA Lon protease, mitochondrial that is encoded in the genome of human. [PRO:DNx, UniProtKB:P36776]Homo sapiens (human)
Nucleoside diphosphate kinase BA nucleoside diphosphate kinase B that is encoded in the genome of human. [PRO:DAN, UniProtKB:P22392]Homo sapiens (human)

Compounds (20)

CompoundDefinitionClassesRoles
thymidine 5'-diphosphatedTDP : A thymidine phosphate having a diphosphate group at the 5'-position.

thymidine 5'-diphosphate: see also record for thymidine 3',5'-diphosphate, RN 2863-04-9
pyrimidine 2'-deoxyribonucleoside 5'-diphosphate;
thymidine phosphate
Escherichia coli metabolite;
mouse metabolite
bortezomibamino acid amide;
L-phenylalanine derivative;
pyrazines
antineoplastic agent;
antiprotozoal drug;
protease inhibitor;
proteasome inhibitor
1-(3,4-dichlorophenyl)-3-(5-pyridin-4-yl-1,3,4-thiadiazol-2-yl)ureaureas
alvocidibalvocidib : A synthetic dihydroxyflavone that is 5,7-dihydroxyflavone which is substituted by a 3-hydroxy-1-methylpiperidin-4-yl group at position 8 and by a chlorine at the 2' position (the (-)-3S,4R stereoisomer). A cyclin-dependent kinase 9 (CDK9) inhibitor, it has been studied for the treatment of acute myeloid leukaemia, arthritis and atherosclerotic plaque formation.

alvocidib: structure given in first source
dihydroxyflavone;
hydroxypiperidine;
monochlorobenzenes;
tertiary amino compound
antineoplastic agent;
antirheumatic drug;
apoptosis inducer;
EC 2.7.11.22 (cyclin-dependent kinase) inhibitor
saracatinibaromatic ether;
benzodioxoles;
diether;
N-methylpiperazine;
organochlorine compound;
oxanes;
quinazolines;
secondary amino compound
anticoronaviral agent;
antineoplastic agent;
apoptosis inducer;
autophagy inducer;
EC 2.7.10.2 (non-specific protein-tyrosine kinase) inhibitor;
radiosensitizing agent
vx 702VX 702: a p38 MAP kinase inhibitorphenylpyridine
chir-265aromatic ether
pf-562,271indoles
buparlisibNVP-BKM120: a pan class I PI3 kinase inhibitor with antineoplastic activity; structure in first sourceaminopyridine;
aminopyrimidine;
morpholines;
organofluorine compound
antineoplastic agent;
EC 2.7.1.137 (phosphatidylinositol 3-kinase) inhibitor
pha 848125N,1,4,4-tetramethyl-8-((4-(4-methylpiperazin-1-yl)phenyl)amino)-4,5-dihydro-1H-pyrazolo(4,3-h)quinazoline-3-carboxamide: a cyclin dependent kinase inhibitor
gdc 0941pictrelisib : A sulfonamide composed of indazole, morpholine, and methylsulfonyl-substituted piperazine rings bound to a thienopyrimidine ring.indazoles;
morpholines;
piperazines;
sulfonamide;
thienopyrimidine
EC 2.7.1.137 (phosphatidylinositol 3-kinase) inhibitor
cudc 1017-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide: a histone deacetylase inhibitor; structure in first source
mln 8237MLN 8237: an aurora kinase A inhibitorbenzazepine
pci 32765ibrutinib : A member of the class of acrylamides that is (3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine in which the piperidine nitrogen is replaced by an acryloyl group. A selective and covalent inhibitor of the enzyme Bruton's tyrosine kinase, it is used for treatment of B-cell malignancies.

ibrutinib: a Btk protein inhibitor
acrylamides;
aromatic amine;
aromatic ether;
N-acylpiperidine;
pyrazolopyrimidine;
tertiary carboxamide
antineoplastic agent;
EC 2.7.10.2 (non-specific protein-tyrosine kinase) inhibitor
tak 733
entrectinibentrectinib : A member of the class of indazoles that is 1H-indazole substituted by [4-(4-methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzoyl]amino and 3,5-difluorobenzyl groups at positions 3 and 5, respectively. It is a potent inhibitor of TRKA, TRKB, TRKC, ROS1, and ALK (IC50 values of 0.1 to 1.7 nM), and used for the treatment of NTRK, ROS1 and ALK gene fusion-positive solid tumours.

entrectinib: inhibits TRK, ROS1, and ALK receptor tyrosine kinases; structure in first source
benzamides;
difluorobenzene;
indazoles;
N-methylpiperazine;
oxanes;
secondary amino compound;
secondary carboxamide
antibacterial agent;
antineoplastic agent;
apoptosis inducer;
EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor
gsk 2126458omipalisib : A member of the class of quinolines that is quinoline which is substituted by pyridazin-4-yl and 5-[(2,4-difluorobenzene-1-sulfonyl)amino]-6-methoxypyridin-3-yl groups at positions 4 and 6, respectively. It is a highly potent inhibitor of PI3K and mTOR developed by GlaxoSmithKline and was previously in human phase 1 clinical trials for the treatment of idiopathic pulmonary fibrosis and solid tumors.

omipalisib: inhibitor of mTOR protein
aromatic ether;
difluorobenzene;
pyridazines;
pyridines;
quinolines;
sulfonamide
anticoronaviral agent;
antineoplastic agent;
autophagy inducer;
EC 2.7.1.137 (phosphatidylinositol 3-kinase) inhibitor;
mTOR inhibitor;
radiosensitizing agent
gsk 1363089GSK 1363089: a multikinase inhibitor that acts on Met, RON, Axl, and VEGFR; structure in first sourcearomatic ether
1-[4-fluoro-3-(trifluoromethyl)phenyl]-3-(5-pyridin-4-yl-1,3,4-thiadiazol-2-yl)ureaureas
osimertinibosimertinib : A member of the class of aminopyrimidines that is 4-(1-methylindol-3-yl)pyrimidin-2-amine in which one of the amino hydrogens is replaced by a 2-methoxy-4-[2-(dimethylamino)ethyl](methyl)amino-5-acrylamidophenyl group. Used (as the mesylate salt) for treatment of EGFR T790M mutation positive non-small cell lung cancer.

osimertinib: an EGFR tyrosine kinase inhibitor
acrylamides;
aminopyrimidine;
biaryl;
indoles;
monomethoxybenzene;
secondary amino compound;
secondary carboxamide;
substituted aniline;
tertiary amino compound
antineoplastic agent;
epidermal growth factor receptor antagonist