9YUZ
Structure of the human 20S proteasome in complex with a beta5-selective covalent syringolin analogue inhibitor.
This is a non-PDB format compatible entry.
Summary for 9YUZ
| Entry DOI | 10.2210/pdb9yuz/pdb |
| EMDB information | 73510 |
| Descriptor | Proteasome subunit alpha type-2, Proteasome subunit beta type-2, Proteasome subunit beta type-5, ... (15 entities in total) |
| Functional Keywords | proteasome, 20s, inhibitor, covalent, hydrolase |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 28 |
| Total formula weight | 762842.76 |
| Authors | Yan, N.L.,Gu, X.,Fajtova, P.,Tse, E.,Melo, A.,Southworth, D.R.,O'Donoghue, A.,Sello, J.K.,Gestwicki, J.E. (deposition date: 2025-10-23, release date: 2026-04-15) |
| Primary citation | Gu, X.,Fajtova, P.,Yan, N.L.,Saxena, A.,Fei, F.,Zhu, J.,Tse, E.,Melo, A.,Yoo, E.,Buchwald, N.H.,Southworth, D.R.,Bogyo, M.,Derisi, J.L.,Gestwicki, J.E.,O'Donoghue, A.J.,Sello, J.K. An Optimized Route to the Syringolin Natural Products Enables Combinatorial Synthesis of Selective, Bioactive Inhibitors of the Plasmodium falciparum 20S Proteasome. J.Med.Chem., 2026 Cited by PubMed Abstract: The syringolin natural products are covalent inhibitors of the 20S proteasome that inspire therapeutic development. Here, we report a new route to the syringolins amenable to solution and solid-phase synthesis that overcomes a problematic macrocyclization. Exploiting our synthetic approach and substrate mimicry models for proteasome inhibition by the syringolins, we generated a collection of hypothetically selective inhibitors of the proteasome, which is an emerging target for antimalarial drugs. We identified compounds from the library having high second-order rate constants for proteasome inhibition and nanomolar antiparasitic activity. They exhibited selectivity for the proteasome over the human proteasome. We solved cryo-EM structures of an inhibitor bound to both 20S proteasomes, revealing key contacts favoring species-selective inhibition. Together, this work provides an improved route to syringolin analogs, sheds new light on substrate mimicry by the syringolins, and provides a structural basis for the pursuit of new antimalarial drugs. PubMed: 41921688DOI: 10.1021/acs.jmedchem.5c03223 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.6 Å) |
Structure validation
Download full validation report
