6GIM

Structure of the DNA duplex d(AAATTT)2 with [N-(3-chloro-4-((4,5-dihydro-1H-imidazol-2-yl)amino)phenyl)-4-((4,5-dihydro-1H-imidazol-2- yl)amino)benzamide] - (drug JNI18)

Summary for 6GIM

• Entry DOI: 10.2210/pdb6gim/pdb
• Descriptor: DNA (5'-D(*AP*AP*AP*TP*TP*T)-3'), [4-[(3-chloranyl-4-imidazolidin-2-ylideneazaniumyl-phenyl)carbamoyl]phenyl]-imidazolidin-2-ylidene-azanium, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: at-rich dna, dna binding drugs, minor groove binding drugs, antiparasitic drugs, trypanosoma brucei, dna
• Biological source: Trypanosoma brucei
• Total number of polymer chains: 4
• Total formula weight: 8501.51

Authors

Millan, C.R.,Dardonvile, C.,de Koning, H.P.,Saperas, N.,Campos, J.L. (deposition date: 2018-05-14, release date: 2018-08-08, Last modification date: 2024-05-01)

Primary citation

Millan, C.R.,Acosta-Reyes, F.J.,Lagartera, L.,Ebiloma, G.U.,Lemgruber, L.,Nue Martinez, J.J.,Saperas, N.,Dardonville, C.,de Koning, H.P.,Campos, J.L.
Functional and structural analysis of AT-specific minor groove binders that disrupt DNA-protein interactions and cause disintegration of the Trypanosoma brucei kinetoplast.
Nucleic Acids Res., 45:8378-8391, 2017

PubMed Abstract: Trypanosoma brucei, the causative agent of sleeping sickness (Human African Trypanosomiasis, HAT), contains a kinetoplast with the mitochondrial DNA (kDNA), comprising of >70% AT base pairs. This has prompted studies of drugs interacting with AT-rich DNA, such as the N-phenylbenzamide bis(2-aminoimidazoline) derivatives 1 [4-((4,5-dihydro-1H-imidazol-2-yl)amino)-N-(4-((4,5-dihydro-1H-imidazol-2-yl)amino)phenyl)benzamide dihydrochloride] and 2 [N-(3-chloro-4-((4,5-dihydro-1H-imidazol-2-yl)amino)phenyl)-4-((4,5-dihydro-1H-imidazol-2-yl)amino)benzamide] as potential drugs for HAT. Both compounds show in vitro effects against T. brucei and in vivo curative activity in a mouse model of HAT. The main objective was to identify their cellular target inside the parasite. We were able to demonstrate that the compounds have a clear effect on the S-phase of T. brucei cell cycle by inflicting specific damage on the kinetoplast. Surface plasmon resonance (SPR)-biosensor experiments show that the drug can displace HMG box-containing proteins essential for kDNA function from their kDNA binding sites. The crystal structure of the complex of the oligonucleotide d[AAATTT]2 with compound 1 solved at 1.25 Å (PDB-ID: 5LIT) shows that the drug covers the minor groove of DNA, displaces bound water and interacts with neighbouring DNA molecules as a cross-linking agent. We conclude that 1 and 2 are powerful trypanocides that act directly on the kinetoplast, a structure unique to the order Kinetoplastida.

PubMed: 28637278
DOI: 10.1093/nar/gkx521

Experimental method

X-RAY DIFFRACTION (1.43 Å)