4hrd

From Proteopedia

Crystal structure of yeast 20S proteasome in complex with the natural product carmaphycin A

PDB ID 4hrd

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Structural highlights

4hrd is a 20 chain structure with sequence from Saccharomyces cerevisiae S288C. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PSA2_YEAST The proteasome degrades poly-ubiquitinated proteins in the cytoplasm and in the nucleus. It is essential for the regulated turnover of proteins and for the removal of misfolded proteins. The proteasome is a multicatalytic proteinase complex that is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. It has an ATP-dependent proteolytic activity.

Publication Abstract from PubMed

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 alpha,beta-unsaturated amide-based inhibitors, is partially reversible and gives insight into the design of proteasome inhibitors for cancer chemotherapy.

Enzyme inhibition by hydroamination: design and mechanism of a hybrid carmaphycin-syringolin enone proteasome inhibitor.,Trivella DB, Pereira AR, Stein ML, Kasai Y, Byrum T, Valeriote FA, Tantillo DJ, Groll M, Gerwick WH, Moore BS Chem Biol. 2014 Jun 19;21(6):782-91. doi: 10.1016/j.chembiol.2014.04.010. Epub, 2014 Jun 12. PMID:24930969^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Trivella DB, Pereira AR, Stein ML, Kasai Y, Byrum T, Valeriote FA, Tantillo DJ, Groll M, Gerwick WH, Moore BS. Enzyme inhibition by hydroamination: design and mechanism of a hybrid carmaphycin-syringolin enone proteasome inhibitor. Chem Biol. 2014 Jun 19;21(6):782-91. doi: 10.1016/j.chembiol.2014.04.010. Epub, 2014 Jun 12. PMID:24930969 doi:http://dx.doi.org/10.1016/j.chembiol.2014.04.010