Page last updated: 2024-10-24

BH3 domain binding

Definition

Target type: molecularfunction

Binding to a BH3 protein domain, present in Bcl-2 family members. The BH3 domain is a potent death domain and has an important role in protein-protein interactions and in cell death. [PMID:11048732, PMID:12133724, PMID:9020082, PMID:9704409, Prosite:PS01259]

BH3 domain binding is a critical molecular function involved in the regulation of apoptosis, a programmed cell death process essential for maintaining tissue homeostasis and removing damaged or unwanted cells. The BH3 domain, a conserved sequence of approximately 25 amino acids, is found in a variety of proteins, including pro-apoptotic Bcl-2 family members, such as Bid, Bax, and Bak. These proteins act as sensors of cellular stress and damage, and their activation triggers the apoptotic cascade.

BH3 domain binding occurs when pro-apoptotic BH3-only proteins interact with anti-apoptotic Bcl-2 family members, such as Bcl-2, Bcl-xL, and Mcl-1. Anti-apoptotic proteins normally inhibit apoptosis by sequestering pro-apoptotic proteins, preventing their activation. However, when cells experience stress, pro-apoptotic BH3-only proteins can bind to the BH3 binding groove of anti-apoptotic proteins, displacing them from the pro-apoptotic proteins and allowing them to initiate apoptosis.

This interaction is highly specific and regulated. Different BH3-only proteins have distinct binding affinities for different anti-apoptotic proteins, contributing to the fine-tuning of the apoptotic response. For example, Bid, a pro-apoptotic protein activated by caspase-8 during the extrinsic apoptosis pathway, preferentially binds to Bcl-xL. This interaction allows Bid to overcome the inhibitory effect of Bcl-xL and promote Bax/Bak activation.

Once bound to their anti-apoptotic targets, BH3-only proteins can trigger a cascade of events that ultimately lead to the formation of pores in the mitochondrial outer membrane. These pores allow the release of cytochrome c and other pro-apoptotic molecules into the cytoplasm, which activate caspases, the executioners of apoptosis.

Therefore, BH3 domain binding plays a crucial role in regulating the balance between life and death in cells. It allows cells to respond appropriately to stress signals, ensuring that damaged or unwanted cells are eliminated while preserving healthy cells. This delicate balance is essential for maintaining tissue homeostasis and preventing diseases such as cancer.'
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Proteins (4)

ProteinDefinitionTaxonomy
Induced myeloid leukemia cell differentiation protein Mcl-1An induced myeloid leukemia cell differentiation protein Mcl-1 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q07820]Homo sapiens (human)
Bcl-2-like protein 1A Bcl-2-like protein 1 that is encoded in the genome of human. [PRO:WCB, UniProtKB:Q07817]Homo sapiens (human)
Apoptosis regulator BAX An apoptosis regulator BAX that is encoded in the genome of human. [PRO:SY, UniProtKB:Q07812]Homo sapiens (human)
Apoptosis regulator Bcl-2An apoptosis regulator Bcl-2 that is encoded in the genome of human. [PRO:WCB, UniProtKB:P10415]Homo sapiens (human)

Compounds (63)

CompoundDefinitionClassesRoles
coumarin2H-chromen-2-one: coumarin derivativecoumarinsfluorescent dye;
human metabolite;
plant metabolite
oxamic acidoxamic acid : A dicarboxylic acid monoamide resulting from the formal condensation of one of the carboxy groups of oxalic acid with ammonia.

Oxamic Acid: Amino-substituted glyoxylic acid derivative.
dicarboxylic acid monoamideEscherichia coli metabolite
catechinhydroxyflavan
hoe 33342BXI-72: structure in first sourcebibenzimidazole;
N-methylpiperazine
fluorochrome
chelerythrinechelerythrine : A benzophenanthridine alkaloid isolated from the root of Zanthoxylum simulans, Chelidonium majus L., and other Papaveraceae.benzophenanthridine alkaloid;
organic cation
antibacterial agent;
antineoplastic agent;
EC 2.7.11.13 (protein kinase C) inhibitor
chlorcyclizinechlorcyclizine: was heading 1964-94 (Prov 1964-73); CHLOROCYCLIZINE & HISTACHLORAZINE were see CHLORCYCLIZINE 1977-94; use PIPERAZINES to search CHLORCYCLIZINE 1966-94; histamine H1-blocker used both orally and topically in allergies and also for the prevention of motion sicknessdiarylmethane
gossypolGossypol: A dimeric sesquiterpene found in cottonseed (GOSSYPIUM). The (-) isomer is active as a male contraceptive (CONTRACEPTIVE AGENTS, MALE) whereas toxic symptoms are associated with the (+) isomer.
sanguinarinebenzophenanthridine alkaloid : A specific group of isoquinoline alkaloids that occur only in higher plants and are constituents mainly of the Papaveraceae family.alkaloid antibiotic;
benzophenanthridine alkaloid;
botanical anti-fungal agent
vorinostatvorinostat : A dicarboxylic acid diamide comprising suberic (octanedioic) acid coupled to aniline and hydroxylamine. A histone deacetylase inhibitor, it is marketed under the name Zolinza for the treatment of cutaneous T cell lymphoma (CTCL).

Vorinostat: A hydroxamic acid and anilide derivative that acts as a HISTONE DEACETYLASE inhibitor. It is used in the treatment of CUTANEOUS T-CELL LYMPHOMA and SEZARY SYNDROME.
dicarboxylic acid diamide;
hydroxamic acid
antineoplastic agent;
apoptosis inducer;
EC 3.5.1.98 (histone deacetylase) inhibitor
alizarindihydroxyanthraquinonechromophore;
dye;
plant metabolite
acenaphthenequinoneacenaphthoquinone : An orthoquinone that is the 1,2-dioxo derivative of acenaphthene.orthoquinoneschain carrier;
epitope
2-phenylphenol2-phenylphenol: RN given refers to parent cpd; structure

biphenyl-2-ol : A member of the class of hydroxybiphenyls that is biphenyl substituted by a hydroxy group at position 2. It is generally used as a post-harvest fungicide for citrus fruits.
hydroxybiphenylsantifungal agrochemical;
environmental food contaminant
4-phenylphenol4-phenylphenol: RN given refers to cpd without isomeric designation

biphenyl-4-ol : A member of the class of hydroxybiphenyls that is biphenyl carrying a hydroxy group at position 4.
hydroxybiphenyls
2-cyanoacetamide2-cyanoacetamide: used in fluorimetric labeling of monosaccharides; structure
scoparonescoparone : A member of the class of coumarins that is esculetin in which the two hydroxy groups at positions 6 and 7 are replaced by methoxy groups. It is a major constituent of the Chinese herbal medicine Yin Chen Hao, and exhibits a variety of pharmacological activities such as anti-inflammatory, anti-allergic, and anti-tumor activities.

scoparone: structure
aromatic ether;
coumarins
anti-allergic agent;
anti-inflammatory agent;
antihypertensive agent;
antilipemic drug;
immunosuppressive agent;
plant metabolite
paclitaxelTaxus: Genus of coniferous yew trees or shrubs, several species of which have medicinal uses. Notable is the Pacific yew, Taxus brevifolia, which is used to make the anti-neoplastic drug taxol (PACLITAXEL).taxane diterpenoid;
tetracyclic diterpenoid
antineoplastic agent;
human metabolite;
metabolite;
microtubule-stabilising agent
epigallocatechin gallate(-)-epigallocatechin 3-gallate : A gallate ester obtained by the formal condensation of gallic acid with the (3R)-hydroxy group of (-)-epigallocatechin.

epigallocatechin gallate: a steroid 5alpha-reductase inhibitor and antimutagen in green tea (Camellia sinensis)
flavans;
gallate ester;
polyphenol
antineoplastic agent;
antioxidant;
apoptosis inducer;
geroprotector;
Hsp90 inhibitor;
neuroprotective agent;
plant metabolite
thiamorpholinethiamorpholine: RN given refers to parent cpd

thiomorpholine : A saturated organic heteromonocyclic parent that is an analogue of morpholine where the oxygen atom is replaced by sulfur.
saturated organic heteromonocyclic parent;
thiomorpholines
5,6,7,8-tetrahydro-1-naphthol5,6,7,8-tetrahydro-1-naphthol : 1-naphthol hydrogenated at C-5, -6, -7 and -8.tetralins
isoscopoletinisoscopoletin : A hydroxycoumarin that is esculetin in which the hydroxy group at position 7 is replaced by a methoxy group. It is the major primary metabolite of scoparone.aromatic ether;
hydroxycoumarin
plant metabolite
epicatechin(-)-epicatechin : A catechin with (2R,3R)-configuration.catechin;
polyphenol
antioxidant
gallocatechol(-)-epigallocatechin : A flavan-3,3',4',5,5',7-hexol having (2R,3R)-configuration.catechin;
flavan-3,3',4',5,5',7-hexol
antioxidant;
food component;
plant metabolite
chelerythrine chloride
indole-2-carboxylic acidindolyl carboxylic acid
benzo(b)thiophene-2-carboxylic acidbenzo(b)thiophene-2-carboxylic acid: for prevention of osteoporosis; structure given in first source
alexidine dihydrchloride
epicatechin gallate(-)-epicatechin-3-O-gallate : A gallate ester obtained by formal condensation of the carboxy group of gallic acid with the (3R)-hydroxy group of epicatechin. A natural product found in Parapiptadenia rigida.

epicatechin gallate: a steroid 5alpha-reductase inhibitor; RN given refers to the (cis)-isomer; structure given in first source; isolated from green tea
catechin;
gallate ester;
polyphenol
EC 3.2.1.1 (alpha-amylase) inhibitor;
EC 3.2.1.20 (alpha-glucosidase) inhibitor;
metabolite
1-(n-dimethyl)amino-7-naphthol
6-n-tridecylsalicylic acid6-n-tridecylsalicylic acid: structure given in first sourcehydroxybenzoic acid
blastmycinblastmycin: structureamidobenzoic acid
resveratroltrans-resveratrol : A resveratrol in which the double bond has E configuration.resveratrolantioxidant;
phytoalexin;
plant metabolite;
quorum sensing inhibitor;
radical scavenger
apogossypolapogossypol: structure in first source
umi-77UMI-77: an Mcl-1 inhibitor; structure in first source
4-(4-ethoxycarbonylanilino)-2-quinazolinecarboxylic acid ethyl esterquinazolines
thioguanine anhydrousThioguanine: An antineoplastic compound which also has antimetabolite action. The drug is used in the therapy of acute leukemia.

tioguanine : A 2-aminopurine that is the 6-thiono derivative of 2-amino-1,9-dihydro-6H-purine. Incorporates into DNA and inhibits synthesis. Used in the treatment of leukaemia.
2-aminopurinesanticoronaviral agent;
antimetabolite;
antineoplastic agent
fraxetinfraxetin : A hydroxycoumarin that is 6-methoxycoumarin in which the hydrogens at positions 7 and 8 have been replaced by hydroxy groups.aromatic ether;
hydroxycoumarin
anti-inflammatory agent;
antibacterial agent;
antimicrobial agent;
antioxidant;
apoptosis inducer;
apoptosis inhibitor;
Arabidopsis thaliana metabolite;
hepatoprotective agent;
hypoglycemic agent
5,6-dehydrokawain5,6-dehydrokawain: from Alpinia speciosa rhizoma; RN given for cpd without isomeric designation; structure given in first source2-pyranones;
aromatic ether
scopoletinhydroxycoumarinplant growth regulator;
plant metabolite
hymecromoneHymecromone: A coumarin derivative possessing properties as a spasmolytic, choleretic and light-protective agent. It is also used in ANALYTICAL CHEMISTRY TECHNIQUES for the determination of NITRIC ACID.hydroxycoumarinantineoplastic agent;
hyaluronic acid synthesis inhibitor
daphnetinhydroxycoumarin
esculetinesculetin : A hydroxycoumarin that is umbelliferone in which the hydrogen at position 6 is substituted by a hydroxy group. It is used in filters for absorption of ultraviolet light.

esculetin: used in filters for absorption of ultraviolet light; structure
hydroxycoumarinantioxidant;
plant metabolite;
ultraviolet filter
7-hydroxycoumarin7-oxycoumarin: derivatives have anti-oxidant properties

umbelliferone : A hydroxycoumarin that is coumarin substituted by a hydroxy group ay position 7.
hydroxycoumarinfluorescent probe;
food component;
plant metabolite
4-methylesculetin4-methylesculetin: has antiinflammatory activity

6,7-dihydroxy-4-methylcoumarin : A hydroxycoumarin that is 4-methylcuomarin which is substituted by hydroxy groups at positions 3 and 4. A hyaluronan synthesis inhibitor. It has also been used as a fluorescent sensor to monitor the consumption of a boronic acid in Suzuki coupling reactions; fluorescence is readily detectable by the naked eye using a standard 365 nm UV lamp.
hydroxycoumarinanti-inflammatory agent;
antioxidant;
hyaluronan synthesis inhibitor
7,8-dihydroxy-4-methylcoumarin7,8-dihydroxy-4-methylcoumarin: possess strong antioxidant and radical scavenging activities; structure in first sourcehydroxycoumarin
kendomycinkendomycin: structure in first sourcebenzofurans
rehmannic acidrehmannic acid: toxic principle, triterpene acid from Lantana camara; RN given refers to (22beta-(Z))-isomer; structure
ixabepilone1,3-thiazoles;
beta-hydroxy ketone;
epoxide;
lactam;
macrocycle
antineoplastic agent;
microtubule-destabilising agent
abt-737aromatic amine;
aryl sulfide;
biphenyls;
C-nitro compound;
monochlorobenzenes;
N-arylpiperazine;
N-sulfonylcarboxamide;
secondary amino compound;
tertiary amino compound
anti-allergic agent;
anti-inflammatory agent;
antineoplastic agent;
apoptosis inducer;
B-cell lymphoma 2 inhibitor
nutlin-3anutlin 3: an MDM2 antagonist; structure in first sourcestilbenoid
N-[4-(2-tert-butylphenyl)sulfonylphenyl]-2,3,4-trihydroxy-5-[(2-propan-2-ylphenyl)methyl]benzamidebenzamides
MI-63MI-63 : An azaspiro compound resulting from the formal fusion of position 3 of 6-chloro-oxindole with position 3 of (2R,3SS5S)-3-(3-chloro-2-fluorophenyl)-5-(2,2-dimethylpropyl)-N-[2-(morpholin-4-yl)ethyl]pyrrolidine-2-carboxamide. It is a potent inhibitor of the MDM2-p53 interaction.azaspiro compound;
monochlorobenzenes;
monofluorobenzenes;
morpholines;
oxindoles;
pyrrolidines;
secondary carboxamide
apoptosis inducer
marinopyrrole a(-)-marinopyrrole A : A member of the class of pyrroles that is 1'H-1,3'-bipyrrole substituted by four chloro groups at positions 4, 4', 5 and 5' and two 2-hydroxybenzoyl moieties at positions 2 and 2'. It is isolated from Streptomyces sp.CNQ-418 and exhibits cytotoxic and antibacterial activities.

marinopyrrole A: antibiotic from a marine Streptomyces sp.; structure in first source
aromatic ketone;
organochlorine compound;
phenols;
pyrroles
antibacterial agent;
antimicrobial agent;
antineoplastic agent;
bacterial metabolite;
marine metabolite
navitoclaxaryl sulfide;
monochlorobenzenes;
morpholines;
N-sulfonylcarboxamide;
organofluorine compound;
piperazines;
secondary amino compound;
sulfone;
tertiary amino compound
antineoplastic agent;
apoptosis inducer;
B-cell lymphoma 2 inhibitor
ethyl 2-amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4h-chromene-3-carboxylateethyl 2-amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate: has antineoplastic activity; structure in first source
meiogynin ameiogynin A: from the bark of Meiogyne cylindrocarpa; structure in first source
abt-199venetoclax : A member of the class of pyrrolopyridines that is a potent inhibitor of the antiapoptotic protein B-cell lymphoma 2. It is used for treamtment of chronic lymphocytic leukemia with 17p deletion.

venetoclax: A BCL-2 inhibitor with antineoplastic activity that is used in the treatment of CHRONIC LYMPHOCYTIC LEUKEMIA associated with chromosome 17p deletion; structure in first source.
aromatic ether;
C-nitro compound;
monochlorobenzenes;
N-alkylpiperazine;
N-arylpiperazine;
N-sulfonylcarboxamide;
oxanes;
pyrrolopyridine
antineoplastic agent;
apoptosis inducer;
B-cell lymphoma 2 inhibitor
nvp-cgm097NVP-CGM097: an MDM2 and HDM2 inhibitor; structure in first source
jy-1-106JY-1-106: a BH3 alpha-helix mimetic that functions as a pan-Bcl-2 inhibitor; structure in first source
a-1155463A-1155463: a Bcl-X(L) inhibitor; structure in first source
bm-1197BM-1197: inhibits both Bcl-xL and Bcl-2; has antineoplastic activity
a-1331852A-1331852: a Bcl-X(L) inhibitor; structure in first source
BDA-366BDA-366 : A member of the class of anthraquinone that is 1,4-diamino-9,10-anthraquinone in which the two amino groups are carrying 3-(diethylamino)-2-hydroxypropyl and (oxiran-2-yl)methyl substituents. It exhibits anti-cancer properties.

BDA-366: has antineoplastic activity; binds Bcl-2 protein; structure in first source
anthraquinone;
epoxide;
secondary alcohol;
secondary amino compound;
tertiary amino compound
antineoplastic agent;
apoptosis inducer
apogossypoloneapogossypolone: has antineoplastic activity; structure in first source