4HRC
Crystal structure of yeast 20S proteasome in complex with epoxyketone carmaphycin analogue 3
Summary for 4HRC
| Entry DOI | 10.2210/pdb4hrc/pdb |
| Related | 4HND 4HNP |
| Related PRD ID | PRD_000930 |
| Descriptor | Proteasome component Y7, Proteasome component C11, Proteasome component PRE2, ... (16 entities in total) |
| Functional Keywords | proteasome, inhibitor, carmaphycin, epoxyketone, vinylketone, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Saccharomyces cerevisiae (Baker's yeast) More |
| Cellular location | Cytoplasm: P23639 P22141 P30656 P23724 P30657 P38624 P23638 P40303 P32379 P40302 P21242 P21243 P25043 P25451 |
| Total number of polymer chains | 28 |
| Total formula weight | 707116.20 |
| Authors | Trivella, D.B.B.,Stein, M.,Groll, M. (deposition date: 2012-10-27, release date: 2014-01-29, Last modification date: 2014-07-02) |
| Primary citation | Trivella, D.B.,Pereira, A.R.,Stein, M.L.,Kasai, Y.,Byrum, T.,Valeriote, F.A.,Tantillo, D.J.,Groll, M.,Gerwick, W.H.,Moore, B.S. Enzyme inhibition by hydroamination: design and mechanism of a hybrid carmaphycin-syringolin enone proteasome inhibitor. Chem.Biol., 21:782-791, 2014 Cited by PubMed Abstract: Hydroamination reactions involving the addition of an amine to an inactivated alkene are entropically prohibited and require strong chemical catalysts. While this synthetic process is efficient at generating substituted amines, there is no equivalent in small molecule-mediated enzyme inhibition. We report an unusual mechanism of proteasome inhibition that involves a hydroamination reaction of alkene derivatives of the epoxyketone natural product carmaphycin. We show that the carmaphycin enone first forms a hemiketal intermediate with the catalytic Thr1 residue of the proteasome before cyclization by an unanticipated intramolecular alkene hydroamination reaction, resulting in a stable six-membered morpholine ring. The carmaphycin enone electrophile, which does not undergo a 1,4-Michael addition as previously observed with vinyl sulfone and α,β-unsaturated amide-based inhibitors, is partially reversible and gives insight into the design of proteasome inhibitors for cancer chemotherapy. PubMed: 24930969DOI: 10.1016/j.chembiol.2014.04.010 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.8 Å) |
Structure validation
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