2FAK
Crystal structure of Salinosporamide A in complex with the yeast 20S proteasome
Summary for 2FAK
| Entry DOI | 10.2210/pdb2fak/pdb |
| Related | 1IRU 1RYP |
| Descriptor | Proteasome component Y7, Proteasome component C11, Proteasome component PRE2, ... (16 entities in total) |
| Functional Keywords | proteasome, ubiquitin, drug design, inhibitor, protease, hydrolase |
| 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 | 705882.23 |
| Authors | Groll, M.,Potts, B.C. (deposition date: 2005-12-07, release date: 2006-04-18, Last modification date: 2024-11-13) |
| Primary citation | Groll, M.,Huber, R.,Potts, B.C. Crystal Structures of Salinosporamide A (NPI-0052) and B (NPI-0047) in Complex with the 20S Proteasome Reveal Important Consequences of beta-Lactone Ring Opening and a Mechanism for Irreversible Binding. J.Am.Chem.Soc., 128:5136-5141, 2006 Cited by PubMed Abstract: The crystal structures of the yeast 20S proteasome core particle (CP) in complex with Salinosporamides A (NPI-0052; 1) and B (4) were solved at <3 angstroms resolution. Each ligand is covalently bound to Thr1O(gamma) via an ester linkage to the carbonyl derived from the beta-lactone ring of the inhibitor. In the case of 1, nucleophilic addition to the beta-lactone ring is followed by addition of C-3O to the chloroethyl group, giving rise to a cyclic ether. The crystal structures were compared to that of the omuralide/CP structure solved previously, and the collective data provide new insights into the mechanism of inhibition and irreversible binding of 1. Upon opening of the beta-lactone ring, C-3O assumes the position occupied by a water molecule in the unligated enzyme and hinders deacylation of the enzyme-ligand complex. Furthermore, the resulting protonation state of Thr1NH2 deactivates the catalytic N-terminus. PubMed: 16608349DOI: 10.1021/ja058320b PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.8 Å) |
Structure validation
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