Mechanism of p300 specific histone acetyltransferase inhibition by small molecules.
Dysfunction of histone acetyltransferases (HATs) leads to several diseases including cancer, diabetes, and asthma. Therefore, small molecule inhibitors and activators of HATs are being considered as new generation therapeutics. Here, we report the molecular mechanisms of p300 HAT inhibition by specific and nonspecific HAT inhibitors: garcinol, isogarcinol, and 1 (LTK14). The p300 specific HAT inhibitor 1 behaves as a noncompetitive inhibitor for both acetyl-CoA and histone, unlike nonspecific HAT inhibitors garcinol and isogarcinol. The isothermal calorimetric data suggest that there is a high affinity enthalpy driven single binding site for 1 on p300HAT domain in contrast to two binding sites for garcinol and isogarcinol. Furthermore, the precise nature of molecular interactions was determined by using fluorescence, docking, and mutational studies. On the basis of these observations, we have proposed the mechanisms of specific versus nonspecific HAT inhibition by these small molecule compounds, which may be useful to design therapeutically favorable HAT inhibitors.
Arif
M
M
Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore 560064, India.
Pradhan
Suman Kalyan
SK
Thanuja
G R
GR
Vedamurthy
B M
BM
Agrawal
Shipra
S
Dasgupta
Dipak
D
Kundu
Tapas K
TK
D002151:Calorimetry; D002942:Circular Dichroism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D016297:Mutagenesis, Site-Directed; D013050:Spectrometry, Fluorescence; D013056:Spectrophotometry, Ultraviolet; D013729:Terpenes / Q000494:pharmacology*; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics; D000099224:p300-CBP-Associated Factor
D004791:Enzyme Inhibitors; D013729:Terpenes; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C054597:garcinol