PDBsum entry 5fmg

Hydrolase

PDB id: 5fmg

Contents

Protein chains

219 a.a.

212 a.a.

220 a.a.

215 a.a.

217 a.a.

219 a.a.

219 a.a.

191 a.a.

186 a.a.

191 a.a.

194 a.a.

189 a.a.

199 a.a.

187 a.a.

Ligands

7F1 ×2

PDB id:

5fmg

Name:

Hydrolase

Title:

Structure and function based design of plasmodium-selective proteasome inhibitors

Structure:

Proteasome subunit alpha, putative. Chain: a, o. Proteasome subunit alpha type 2, putative. Chain: b, p. Proteasome subunit alpha type. Chain: c, q. Proteasome subunit alpha type. Chain: d, r. Proteasome subunit alpha type.

Source:

Plasmodium falciparum. Organism_taxid: 5833. Organism_taxid: 5833

Authors:

H.Li,A.J.O'Donoghue,W.A.Van Der Linden,S.C.Xie,E.Yoo,I.T.Foe, L.Tilley,C.S.Craik,P.C.A.Da Fonseca,M.Bogyo

Key ref:

H.Li et al. (2016). Structure- and function-based design of Plasmodium-selective proteasome inhibitors. Nature, 530, 233-236. PubMed id: 26863983 DOI: 10.1038/nature16936

Date:

04-Nov-15 Release date: 02-Mar-16

Protein chains

Q8IAR3  (Q8IAR3_PLAF7) -  Proteasome subunit alpha type-6, putative from Plasmodium falciparum (isolate 3D7)

Seq: 260 a.a.

Struc: 219 a.a.

Protein chains

C6KST3  (C6KST3_PLAF7) -  Proteasome subunit alpha type-2, putative from Plasmodium falciparum (isolate 3D7)

Seq: 235 a.a.

Struc: 212 a.a.

Protein chains

Q8IDG3  (Q8IDG3_PLAF7) -  Proteasome subunit alpha type from Plasmodium falciparum (isolate 3D7)

Seq: 246 a.a.

Struc: 220 a.a.

Protein chains

Q8IDG2  (Q8IDG2_PLAF7) -  Proteasome subunit alpha type from Plasmodium falciparum (isolate 3D7)

Seq: 241 a.a.

Struc: 215 a.a.

Protein chains

Q8IBI3  (Q8IBI3_PLAF7) -  Proteasome subunit alpha type from Plasmodium falciparum (isolate 3D7)

Seq: 256 a.a.

Struc: 217 a.a.

Protein chains

Q8IK90  (Q8IK90_PLAF7) -  Proteasome subunit alpha type-1, putative from Plasmodium falciparum (isolate 3D7)

Seq: 254 a.a.

Struc: 219 a.a.

Protein chains

O77396  (O77396_PLAF7) -  Proteasome subunit alpha type-3, putative from Plasmodium falciparum (isolate 3D7)

Seq: 252 a.a.

Struc: 219 a.a.

Protein chains

Q8I0U7  (Q8I0U7_PLAF7) -  Proteasome subunit beta type-6, putative from Plasmodium falciparum (isolate 3D7)

Seq: 282 a.a.

Struc: 191 a.a.

Protein chains

Q8I6T3  (Q8I6T3_PLAF7) -  Proteasome subunit beta from Plasmodium falciparum (isolate 3D7)

Seq: 270 a.a.

Struc: 186 a.a.

Protein chains

Q8I261  (Q8I261_PLAF7) -  Proteasome subunit beta from Plasmodium falciparum (isolate 3D7)

Seq: 218 a.a.

Struc: 191 a.a.

Protein chains

Q8IKC9  (Q8IKC9_PLAF7) -  Proteasome subunit beta from Plasmodium falciparum (isolate 3D7)

Seq: 195 a.a.

Struc: 194 a.a.

Protein chains

Q8IJT1  (Q8IJT1_PLAF7) -  Proteasome subunit beta from Plasmodium falciparum (isolate 3D7)

Seq: 271 a.a.

Struc: 189 a.a.

Protein chains

No UniProt id for this chain

Struc: 199 a.a.

Protein chains

Q7K6A9  (Q7K6A9_PLAF7) -  Proteasome subunit beta from Plasmodium falciparum (isolate 3D7)

Seq: 265 a.a.

Struc: 187 a.a.

Enzyme reactions

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

DOI no: 10.1038/nature16936

Nature 530:233-236 (2016)

PubMed id: 26863983

Structure- and function-based design of Plasmodium-selective proteasome inhibitors.

H.Li, A.J.O'Donoghue, W.A.van der Linden, S.C.Xie, E.Yoo, I.T.Foe, L.Tilley, C.S.Craik, P.C.da Fonseca, M.Bogyo.

ABSTRACT

The proteasome is a multi-component protease complex responsible for regulating key processes such as the cell cycle and antigen presentation. Compounds that target the proteasome are potentially valuable tools for the treatment of pathogens that depend on proteasome function for survival and replication. In particular, proteasome inhibitors have been shown to be toxic for the malaria parasite Plasmodium falciparum at all stages of its life cycle. Most compounds that have been tested against the parasite also inhibit the mammalian proteasome, resulting in toxicity that precludes their use as therapeutic agents. Therefore, better definition of the substrate specificity and structural properties of the Plasmodium proteasome could enable the development of compounds with sufficient selectivity to allow their use as anti-malarial agents. To accomplish this goal, here we use a substrate profiling method to uncover differences in the specificities of the human and P. falciparum proteasome. We design inhibitors based on amino-acid preferences specific to the parasite proteasome, and find that they preferentially inhibit the β2-subunit. We determine the structure of the P. falciparum 20S proteasome bound to the inhibitor using cryo-electron microscopy and single-particle analysis, to a resolution of 3.6 Å. These data reveal the unusually open P. falciparum β2 active site and provide valuable information about active-site architecture that can be used to further refine inhibitor design. Furthermore, consistent with the recent finding that the proteasome is important for stress pathways associated with resistance of artemisinin family anti-malarials, we observe growth inhibition synergism with low doses of this β2-selective inhibitor in artemisinin-sensitive and -resistant parasites. Finally, we demonstrate that a parasite-selective inhibitor could be used to attenuate parasite growth in vivo without appreciable toxicity to the host. Thus, the Plasmodium proteasome is a chemically tractable target that could be exploited by next-generation anti-malarial agents.