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TitleModulation of ABCG2 Transporter Activity by Ko143 Derivatives.
Journal, issue, pagesACS Chem Biol, Vol. 19, Issue 11, Page 2304-2313, Year 2024
Publish dateNov 15, 2024
AuthorsQin Yu / Sepehr Dehghani-Ghahnaviyeh / Ali Rasouli / Anna Sadurni / Julia Kowal / Rose Bang-Soerensen / Po-Chao Wen / Melanie Tinzl-Zechner / Rossitza N Irobalieva / Dongchun Ni / Henning Stahlberg / Karl-Heinz Altmann / Emad Tajkhorshid / Kaspar P Locher /
PubMed AbstractABCG2 is a multidrug transporter that protects tissues from xenobiotics, affects drug pharmacokinetics, and contributes to multidrug resistance of cancer cells. Here, we present tetracyclic ...ABCG2 is a multidrug transporter that protects tissues from xenobiotics, affects drug pharmacokinetics, and contributes to multidrug resistance of cancer cells. Here, we present tetracyclic fumitremorgin C analog Ko143 derivatives, evaluate their modulation of purified ABCG2, and report four high-resolution cryo-EM structures and computational analyses to elucidate their interactions with ABCG2. We found that Ko143 derivatives that are based on a ring-opened scaffold no longer inhibit ABCG2-mediated transport activity. In contrast, closed-ring, tetracyclic analogs were highly potent inhibitors. Strikingly, the least potent of these compounds, MZ82, bound deeper into the central ABCG2 cavity than the other inhibitors and it led to partial closure of the transmembrane domains and increased flexibility of the nucleotide-binding domains. Minor structural modifications can thus convert a potent inhibitor into a compound that induces conformational changes in ABCG2 similar to those observed during binding of a substrate. Molecular dynamics simulations and free energy binding calculations further supported the correlation between reduced potency and distinct binding pose of the compounds. We introduce the highly potent inhibitor AZ99 that may exhibit improved stability.
External linksACS Chem Biol / PubMed:39445888 / PubMed Central
MethodsEM (single particle)
Resolution2.39 - 3.0 Å
Structure data

18003

8pxo

EMDB-18003, PDB-8pxo:
ABCG2 in complex with AZ99 and 5D3 Fab
Method: EM (single particle) / Resolution: 3.0 Å

18016

8py4

EMDB-18016, PDB-8py4:
ABCG2 in complex with ko143 and 5D3 Fab
Method: EM (single particle) / Resolution: 3.0 Å

18210

8q7b

EMDB-18210, PDB-8q7b:
ABCG2 in complex with MZ29 and 5D3 Fab
Method: EM (single particle) / Resolution: 2.56 Å

18330

8qcm

EMDB-18330, PDB-8qcm:
ABCG2 in complex with MZ82 and 5D3 Fab
Method: EM (single particle) / Resolution: 2.39 Å

Chemicals

ChemComp-CLR:
CHOLESTEROL


ChemComp, No image

ChemComp-I3T:
Unknown entry


ChemComp, No image

ChemComp-I3O:
Unknown entry

ChemComp-HOH:
WATER

ChemComp-BWQ:
~{tert}-butyl 3-[(2~{S},5~{S},8~{S})-14-cyclopentyloxy-2-(2-methylpropyl)-4,7-bis(oxidanylidene)-3,6,17-triazatetracyclo[8.7.0.0^{3,8}.0^{11,16}]heptadeca-1(10),11,13,15-tetraen-5-yl]propanoate


ChemComp, No image

ChemComp-V0U:
Unknown entry

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsTRANSPORT PROTEIN / Multidrug transporter / ABC transporter / multidrug resistance

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