3GPT

Crystal structure of the yeast 20S proteasome in complex with Salinosporamide derivatives: slow substrate ligand

Summary for 3GPT

• Entry DOI: 10.2210/pdb3gpt/pdb
• Related: 1ryp 2fak 3GPJ 3GPW
• Descriptor: Proteasome component Y7, Proteasome component C11, Proteasome component PRE2, ... (16 entities in total)
• Functional Keywords: proteasome, ubiquitin, cancer therapy, inhibitor, immunology, time dependent leaving group elimination, cytoplasm, hydrolase, nucleus, phosphoprotein, protease, threonine protease, isopeptide bond, ubl conjugation, zymogen
• Biological source: Saccharomyces cerevisiae (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: 706002.27

Authors

Groll, M.,Macherla, V.R.,Manam, R.R.,Arthur, K.A.M.,Potts, C.B. (deposition date: 2009-03-23, release date: 2009-09-15, Last modification date: 2024-11-06)

Primary citation

Groll, M.,McArthur, K.A.,Macherla, V.R.,Manam, R.R.,Potts, B.C.
Snapshots of the fluorosalinosporamide/20S complex offer mechanistic insights for fine tuning proteasome inhibition
J.Med.Chem., 52:5420-5428, 2009

PubMed Abstract: Many marketed drugs contain fluorine, reflecting its ability to modulate a variety of biological responses. The unique 20S proteasome inhibition profile of fluorosalinosporamide compared to chlorinated anticancer agent salinosporamide A (NPI-0052) is exemplary and relates to each halogen's leaving group potential. Crystal structures of fluoro-, hydroxy-, and bromosalinosporamide in complex with the yeast 20S proteasome core particle (CP) provide mechanistic insights into ligand binding and leaving group elimination and the ability to fine-tune the duration of proteasome inhibition. Fluorosalinosporamide/CP crystal structures determined over time offer striking snapshots of the ligand trapped with an intact fluoroethyl group in anticipation of fluoride elimination, followed by complete nucleophilic displacement of fluoride to give the highly stabilized cyclic ether found for salinosporamide A and bromosalinosporamide. This two-step reaction pathway is consistent with a mechanism for partially reversible proteasome inhibition by fluorosalinosporamide. Proteasome catalyzed fluoride displacement provides preliminary insights into the active site Thr1N pK(a).

PubMed: 19678642
DOI: 10.1021/jm900559x

Experimental method

X-RAY DIFFRACTION (2.41 Å)