8QCM
ABCG2 in complex with MZ82 and 5D3 Fab
Summary for 8QCM
| Entry DOI | 10.2210/pdb8qcm/pdb |
| EMDB information | 18003 18016 18330 |
| Descriptor | Broad substrate specificity ATP-binding cassette transporter ABCG2, 5D3(Fab) light chain variable domain, 5D3(Fab) heavy chain variable domain, ... (7 entities in total) |
| Functional Keywords | abc transporter, multidrug resistance, transport protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 6 |
| Total formula weight | 245960.95 |
| Authors | Yu, Q.,Kowal, J.,Ni, D.,Stahlberg, H.,Tajkhorshid, E.,Altmann, K.H.,Locher, K.P. (deposition date: 2023-08-27, release date: 2024-11-06, Last modification date: 2024-11-27) |
| Primary citation | Yu, Q.,Dehghani-Ghahnaviyeh, S.,Rasouli, A.,Sadurni, A.,Kowal, J.,Bang-Soerensen, R.,Wen, P.C.,Tinzl-Zechner, M.,Irobalieva, R.N.,Ni, D.,Stahlberg, H.,Altmann, K.H.,Tajkhorshid, E.,Locher, K.P. Modulation of ABCG2 Transporter Activity by Ko143 Derivatives. Acs Chem.Biol., 19:2304-2313, 2024 Cited by PubMed Abstract: 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. PubMed: 39445888DOI: 10.1021/acschembio.4c00353 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.39 Å) |
Structure validation
Download full validation report
