PDBsum entry 6e5b

Hydrolase

PDB id: 6e5b

Contents

Protein chains

229 a.a.

245 a.a.

227 a.a.

230 a.a.

236 a.a.

244 a.a.

241 a.a.

218 a.a.

204 a.a.

196 a.a.

203 a.a.

213 a.a.

214 a.a.

199 a.a.

Ligands

SCN ×3

HUJ ×4

Metals

_NA ×12

Waters ×63

PDB id:

6e5b

Name:

Hydrolase

Title:

Human immunoproteasome 20s particle in complex with compound 1

Structure:

Proteasome subunit alpha type-2. Chain: a, o. Synonym: macropain subunit c3,multicatalytic endopeptidase complex subunit c3,proteasome component c3. Proteasome subunit alpha type-4. Chain: b, p. Synonym: macropain subunit c9,multicatalytic endopeptidase complex subunit c9,proteasome component c9,proteasome subunit l. Proteasome subunit alpha type-7.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Organism_taxid: 9606

Resolution:

2.77Å R-factor: 0.248 R-free: 0.292

Authors:

S.Steinbacher,M.Augustin,M.Blaesse,S.F.Harris

Key ref:

E.Ladi et al. (2019). Design and Evaluation of Highly Selective Human Immunoproteasome Inhibitors Reveal a Compensatory Process That Preserves Immune Cell Viability. J Med Chem, 62, 7032-7041. PubMed id: 31283222 DOI: 10.1021/acs.jmedchem.9b00509

Date:

19-Jul-18 Release date: 11-Sep-19

Protein chains

P25787  (PSA2_HUMAN) -  Proteasome subunit alpha type-2 from Homo sapiens

Seq: 234 a.a.

Struc: 229 a.a.

Protein chains

P25789  (PSA4_HUMAN) -  Proteasome subunit alpha type-4 from Homo sapiens

Seq: 261 a.a.

Struc: 245 a.a.

Protein chains

O14818  (PSA7_HUMAN) -  Proteasome subunit alpha type-7 from Homo sapiens

Seq: 248 a.a.

Struc: 227 a.a.

Protein chains

P28066  (PSA5_HUMAN) -  Proteasome subunit alpha type-5 from Homo sapiens

Seq: 241 a.a.

Struc: 230 a.a.

Protein chains

P25786  (PSA1_HUMAN) -  Proteasome subunit alpha type-1 from Homo sapiens

Seq: 263 a.a.

Struc: 236 a.a.

Protein chains

P25788  (PSA3_HUMAN) -  Proteasome subunit alpha type-3 from Homo sapiens

Seq: 255 a.a.

Struc: 244 a.a.

Protein chains

P60900  (PSA6_HUMAN) -  Proteasome subunit alpha type-6 from Homo sapiens

Seq: 246 a.a.

Struc: 241 a.a.

Protein chains

P40306  (PSB10_HUMAN) -  Proteasome subunit beta type-10 from Homo sapiens

Seq: 273 a.a.

Struc: 218 a.a.

Protein chains

P49720  (PSB3_HUMAN) -  Proteasome subunit beta type-3 from Homo sapiens

Seq: 205 a.a.

Struc: 204 a.a.

Protein chains

P49721  (PSB2_HUMAN) -  Proteasome subunit beta type-2 from Homo sapiens

Seq: 201 a.a.

Struc: 196 a.a.

Protein chains

P28062  (PSB8_HUMAN) -  Proteasome subunit beta type-8 from Homo sapiens

Seq: 276 a.a.

Struc: 203 a.a.

Protein chains

P20618  (PSB1_HUMAN) -  Proteasome subunit beta type-1 from Homo sapiens

Seq: 241 a.a.

Struc: 213 a.a.

Protein chains

P28070  (PSB4_HUMAN) -  Proteasome subunit beta type-4 from Homo sapiens

Seq: 264 a.a.

Struc: 214 a.a.

Protein chains

P28065  (PSB9_HUMAN) -  Proteasome subunit beta type-9 from Homo sapiens

Seq: 219 a.a.

Struc: 199 a.a.

Enzyme reactions

• Enzyme class: Chains A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, W, X, Y, Z, a, b: E.C.3.4.25.1 - proteasome endopeptidase complex.
• Reaction: Cleavage at peptide bonds with very broad specificity.

DOI no: 10.1021/acs.jmedchem.9b00509

J Med Chem 62:7032-7041 (2019)

PubMed id: 31283222

Design and Evaluation of Highly Selective Human Immunoproteasome Inhibitors Reveal a Compensatory Process That Preserves Immune Cell Viability.

E.Ladi, C.Everett, C.E.Stivala, B.E.Daniels, M.R.Durk, S.F.Harris, M.P.Huestis, H.E.Purkey, S.T.Staben, M.Augustin, M.Blaesse, S.Steinbacher, C.Eidenschenk, R.Pappu, M.Siu.

ABSTRACT

The pan-proteasome inhibitor bortezomib demonstrated clinical efficacy in off-label trials of Systemic Lupus Erythematosus. One potential mechanism of this clinical benefit is from the depletion of pathogenic immune cells (plasmablasts and plasmacytoid dendritic cells). However, bortezomib is cytotoxic against nonimmune cells, which limits its use for autoimmune diseases. An attractive alternative is to selectively inhibit the immune cell-specific immunoproteasome to deplete pathogenic immune cells and spare nonhematopoietic cells. Here, we disclose the development of highly subunit-selective immunoproteasome inhibitors using insights obtained from the first bona fide human immunoproteasome cocrystal structures. Evaluation of these inhibitors revealed that immunoproteasome-specific inhibition does not lead to immune cell death as anticipated and that targeting viability requires inhibition of both immuno- and constitutive proteasomes. CRISPR/Cas9-mediated knockout experiments confirmed upregulation of the constitutive proteasome upon disruption of the immunoproteasome, protecting cells from death. Thus, immunoproteasome inhibition alone is not a suitable approach to deplete immune cells.