PDBsum entry 5m32

Hydrolase

PDB id: 5m32

Contents

Protein chains

230 a.a.

234 a.a.

234 a.a.

233 a.a.

234 a.a.

232 a.a.

233 a.a.

221 a.a.

204 a.a.

196 a.a.

200 a.a.

213 a.a.

216 a.a.

202 a.a.

347 a.a.

333 a.a.

361 a.a.

348 a.a.

363 a.a.

332 a.a.

230 a.a.

155 a.a.

364 a.a.

415 a.a.

375 a.a.

206 a.a.

75 a.a.

101 a.a.

259 a.a.

26 a.a.

Ligands

GLN-VAL-ILE-GLU-TYR

MET-ILE-VAL

6V9-7C9-7C9-6VA ×2

ADP ×6

PDB id:

5m32

Name:

Hydrolase

Title:

Human 26s proteasome in complex with oprozomib

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. Synthetic: yes. Synthetic construct. Organism_taxid: 32630

Authors:

D.Haselbach,J.Schrader,F.Lambrecht,F.Henneberg,A.Chari,H.Stark

Key ref:

D.Haselbach et al. (2017). Long-range allosteric regulation of the human 26S proteasome by 20S proteasome-targeting cancer drugs. Nat Commun, 8, 15578. PubMed id: 28541292

Date:

14-Oct-16 Release date: 05-Jul-17

Protein chains

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

Seq: 234 a.a.

Struc: 230 a.a.

Protein chains

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

Seq: 261 a.a.

Struc: 234 a.a.

Protein chains

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

Seq: 248 a.a.

Struc: 234 a.a.*

Protein chains

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

Seq: 241 a.a.

Struc: 233 a.a.

Protein chains

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

Seq: 263 a.a.

Struc: 234 a.a.*

Protein chains

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

Seq: 255 a.a.

Struc: 232 a.a.

Protein chains

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

Seq: 246 a.a.

Struc: 233 a.a.

Protein chains

Q99436  (PSB7_HUMAN) -  Proteasome subunit beta type-7 from Homo sapiens

Seq: 277 a.a.

Struc: 221 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

P28074  (PSB5_HUMAN) -  Proteasome subunit beta type-5 from Homo sapiens

Seq: 263 a.a.

Struc: 200 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: 216 a.a.

Protein chains

P28072  (PSB6_HUMAN) -  Proteasome subunit beta type-6 from Homo sapiens

Seq: 239 a.a.

Struc: 202 a.a.*

Protein chain

P35998  (PRS7_HUMAN) -  26S proteasome regulatory subunit 7 from Homo sapiens

Seq: 433 a.a.

Struc: 347 a.a.

Protein chain

P62191  (PRS4_HUMAN) -  26S proteasome regulatory subunit 4 from Homo sapiens

Seq: 440 a.a.

Struc: 333 a.a.

Protein chain

P43686  (PRS6B_HUMAN) -  26S proteasome regulatory subunit 6B from Homo sapiens

Seq: 418 a.a.

Struc: 361 a.a.

Protein chain

P62333  (PRS10_HUMAN) -  26S proteasome regulatory subunit 10B from Homo sapiens

Seq: 389 a.a.

Struc: 348 a.a.

Protein chain

P17980  (PRS6A_HUMAN) -  26S proteasome regulatory subunit 6A from Homo sapiens

Seq: 439 a.a.

Struc: 363 a.a.

Protein chain

P62195  (PRS8_HUMAN) -  26S proteasome regulatory subunit 8 from Homo sapiens

Seq: 406 a.a.

Struc: 332 a.a.

Protein chain

Q99460  (PSMD1_HUMAN) -  26S proteasome non-ATPase regulatory subunit 1 from Homo sapiens

Seq: 953 a.a.

Struc: 230 a.a.

Protein chain

O43242  (PSMD3_HUMAN) -  26S proteasome non-ATPase regulatory subunit 3 from Homo sapiens

Seq: 534 a.a.

Struc: 155 a.a.

Protein chain

O00232  (PSD12_HUMAN) -  26S proteasome non-ATPase regulatory subunit 12 from Homo sapiens

Seq: 456 a.a.

Struc: 364 a.a.*

Protein chain

O00231  (PSD11_HUMAN) -  26S proteasome non-ATPase regulatory subunit 11 from Homo sapiens

Seq: 422 a.a.

Struc: 415 a.a.

Protein chain

Q15008  (PSMD6_HUMAN) -  26S proteasome non-ATPase regulatory subunit 6 from Homo sapiens

Seq: 389 a.a.

Struc: 375 a.a.

Protein chain

P51665  (PSMD7_HUMAN) -  26S proteasome non-ATPase regulatory subunit 7 from Homo sapiens

Seq: 324 a.a.

Struc: 206 a.a.

Protein chain

Q9UNM6  (PSD13_HUMAN) -  26S proteasome non-ATPase regulatory subunit 13 from Homo sapiens

Seq: 376 a.a.

Struc: 75 a.a.

Protein chain

P55036  (PSMD4_HUMAN) -  26S proteasome non-ATPase regulatory subunit 4 from Homo sapiens

Seq: 377 a.a.

Struc: 101 a.a.*

Protein chain

O00487  (PSDE_HUMAN) -  26S proteasome non-ATPase regulatory subunit 14 from Homo sapiens

Seq: 310 a.a.

Struc: 259 a.a.

Protein chain

P60896  (SEM1_HUMAN) -  26S proteasome complex subunit SEM1 from Homo sapiens

Seq: 70 a.a.

Struc: 26 a.a.

* PDB and UniProt seqs differ at 20 residue positions (black crosses)

Enzyme reactions

• Enzyme class 2: 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.
• Enzyme class 3: Chain q: E.C.3.4.19.- - ?????

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Nat Commun 8:15578 (2017)

PubMed id: 28541292

Long-range allosteric regulation of the human 26S proteasome by 20S proteasome-targeting cancer drugs.

D.Haselbach, J.Schrader, F.Lambrecht, F.Henneberg, A.Chari, H.Stark.

ABSTRACT

The proteasome holoenzyme is the major non-lysosomal protease; its proteolytic activity is essential for cellular homeostasis. Thus, it is an attractive target for the development of chemotherapeutics. While the structural basis of core particle (CP) inhibitors is largely understood, their structural impact on the proteasome holoenzyme remains entirely elusive. Here, we determined the structure of the 26S proteasome with and without the inhibitor Oprozomib. Drug binding modifies the energy landscape of conformational motion in the proteasome regulatory particle (RP). Structurally, the energy barrier created by Oprozomib triggers a long-range allosteric regulation, resulting in the stabilization of a non-productive state. Thereby, the chemical drug-binding signal is converted, propagated and amplified into structural changes over a distance of more than 150 Å from the proteolytic site to the ubiquitin receptor Rpn10. The direct visualization of changes in conformational dynamics upon drug binding allows new ways to screen and develop future allosteric proteasome inhibitors.