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PDBsum entry 2fhh
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Hydrolase PDB id
2fhh

 

 

 

 

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Contents
Protein chains
(+ 8 more) 220 a.a. *
(+ 8 more) 222 a.a. *
Ligands
M1N ×14
Waters ×321
* Residue conservation analysis
PDB id:
2fhh
Name: Hydrolase
Title: Crystal structure of mycobacterium tuberculosis proteasome in complex with a peptidyl boronate inhibitor mln-273
Structure: 20s proteasome, alpha and beta subunits. Chain: a, b, d, f, i, k, m, o, q, s, u, w, y, 1. Engineered: yes. Proteasome, beta subunit. Chain: h, c, e, g, j, l, n, p, r, t, v, x, z, 2. Engineered: yes
Source: Mycobacterium tuberculosis. Organism_taxid: 1773. Gene: prca. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Gene: prcb.
Biol. unit: 28mer (from PQS)
Resolution:
2.99Å     R-factor:   0.228     R-free:   0.262
Authors: H.Li
Key ref: G.Hu et al. (2006). Structure of the Mycobacterium tuberculosis proteasome and mechanism of inhibition by a peptidyl boronate. Mol Microbiol, 59, 1417-1428. PubMed id: 16468986
Date:
23-Dec-05     Release date:   28-Feb-06    
PROCHECK
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 Headers
 References

Protein chains
Pfam   ArchSchema ?
P9WHU1  (PSA_MYCTU) -  Proteasome subunit alpha from Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
Seq:
Struc: 		248 a.a.
220 a.a.
Protein chains
Pfam   ArchSchema ?
P9WHT9  (PSB_MYCTU) -  Proteasome subunit beta from Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
Seq:
Struc: 		291 a.a.
222 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains H, C, E, G, J, L, N, P, R, T, V, X, Z, 2: E.C.3.4.25.1  - proteasome endopeptidase complex.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Cleavage at peptide bonds with very broad specificity.

 

 
Mol Microbiol 59:1417-1428 (2006)
PubMed id: 16468986  
 
 
Structure of the Mycobacterium tuberculosis proteasome and mechanism of inhibition by a peptidyl boronate.
G.Hu, G.Lin, M.Wang, L.Dick, R.M.Xu, C.Nathan, H.Li.
 
  ABSTRACT  
 
Mycobacterium tuberculosis (Mtb) has the remarkable ability to resist killing by human macrophages. The 750 kDa proteasome, not available in most eubacteria except Actinomycetes, appears to contribute to Mtb's resistance. The crystal structure of the Mtb proteasome at 3.0 A resolution reveals a substrate-binding pocket with composite features of the distinct beta1, beta2 and beta5 substrate binding sites of eukaryotic proteasomes, accounting for the broad specificity of the Mtb proteasome towards oligopeptides described in the companion article [Lin et al. (2006), Mol Microbiol doi:10.1111/j.1365-2958.2005.05035.x]. The substrate entrance at the end of the cylindrical proteasome appears open in the crystal structure due to partial disorder of the alpha-subunit N-terminal residues. However, cryo-electron microscopy of the core particle reveals a closed end, compatible with the density observed in negative-staining electron microscopy that depended on the presence of the N-terminal octapetides of the alpha-subunits in the companion article, suggesting that the Mtb proteasome has a gated structure. We determine for the first time the proteasomal inhibition mechanism of the dipeptidyl boronate N-(4-morpholine)carbonyl-beta-(1-naphthyl)-L-alanine-L-leucine boronic acid (MLN-273), an analogue of the antimyeloma drug bortezomib. The structure improves prospects for designing Mtb-specific proteasomal inhibitors as a novel approach to chemotherapy of tuberculosis.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
22183254 J.Maupin-Furlow (2012).
Proteasomes and protein conjugation across domains of life.
  Nat Rev Microbiol, 10, 100-111.  
22020261 E.Gur, D.Biran, and E.Z.Ron (2011).
Regulated proteolysis in Gram-negative bacteria--how and when?
  Nat Rev Microbiol, 9, 839-848.  
21151032 L.Bedford, J.Lowe, L.R.Dick, R.J.Mayer, and J.E.Brownell (2011).
Ubiquitin-like protein conjugation and the ubiquitin-proteasome system as drug targets.
  Nat Rev Drug Discov, 10, 29-46.  
20203624 F.Striebel, M.Hunkeler, H.Summer, and E.Weber-Ban (2010).
The mycobacterial Mpa-proteasome unfolds and degrades pupylated substrates by engaging Pup's N-terminus.
  EMBO J, 29, 1262-1271.  
20109157 K.E.Burns, and K.H.Darwin (2010).
Pupylation versus ubiquitylation: tagging for proteasome-dependent degradation.
  Cell Microbiol, 12, 424-431.  
20711362 S.Gandotra, M.B.Lebron, and S.Ehrt (2010).
The Mycobacterium tuberculosis proteasome active site threonine is essential for persistence yet dispensable for replication and resistance to nitric oxide.
  PLoS Pathog, 6, 0.  
20953180 T.Wang, K.H.Darwin, and H.Li (2010).
Binding-induced folding of prokaryotic ubiquitin-like protein on the Mycobacterium proteasomal ATPase targets substrates for degradation.
  Nat Struct Mol Biol, 17, 1352-1357.
PDB codes: 3m91 3m9b 3m9d 3m9h
19671445 F.Cerda-Maira, and K.H.Darwin (2009).
The Mycobacterium tuberculosis proteasome: more than just a barrel-shaped protease.
  Microbes Infect, 11, 1150-1155.  
19759536 G.Lin, D.Li, L.P.de Carvalho, H.Deng, H.Tao, G.Vogt, K.Wu, J.Schneider, T.Chidawanyika, J.D.Warren, H.Li, and C.Nathan (2009).
Inhibitors selective for mycobacterial versus human proteasomes.
  Nature, 461, 621-626.
PDB codes: 3h6f 3h6i 3hf9 3hfa
19924240 H.J.Kimura, C.Y.Chen, S.C.Tzou, R.Rocchi, M.A.Landek-Salgado, K.Suzuki, M.Kimura, N.R.Rose, and P.Caturegli (2009).
Immunoproteasome overexpression underlies the pathogenesis of thyroid oncocytes and primary hypothyroidism: studies in humans and mice.
  PLoS One, 4, e7857.  
19028679 K.E.Burns, W.T.Liu, H.I.Boshoff, P.C.Dorrestein, and C.E.Barry (2009).
Proteasomal Protein Degradation in Mycobacteria Is Dependent upon a Prokaryotic Ubiquitin-like Protein.
  J Biol Chem, 284, 3069-3075.  
19483713 K.H.Darwin (2009).
Prokaryotic ubiquitin-like protein (Pup), proteasomes and pathogenesis.
  Nat Rev Microbiol, 7, 485-491.  
19376868 M.A.Humbard, G.Zhou, and J.A.Maupin-Furlow (2009).
The N-terminal penultimate residue of 20S proteasome alpha1 influences its N(alpha) acetylation and protein levels as well as growth rate and stress responses of Haloferax volcanii.
  J Bacteriol, 191, 3794-3803.  
19580545 S.Liao, Q.Shang, X.Zhang, J.Zhang, C.Xu, and X.Tu (2009).
Pup, a prokaryotic ubiquitin-like protein, is an intrinsically disordered protein.
  Biochem J, 422, 207-215.  
19836337 T.Wang, H.Li, G.Lin, C.Tang, D.Li, C.Nathan, K.H.Darwin, and H.Li (2009).
Structural insights on the Mycobacterium tuberculosis proteasomal ATPase Mpa.
  Structure, 17, 1377-1385.
PDB code: 3fp9
18829465 G.Lin, C.Tsu, L.Dick, X.K.Zhou, and C.Nathan (2008).
Distinct Specificities of Mycobacterium tuberculosis and Mammalian Proteasomes for N-Acetyl Tripeptide Substrates.
  J Biol Chem, 283, 34423-34431.  
  18931431 K.Felderer, M.Groves, J.Diez, E.Pohl, and S.Witt (2008).
Crystallization and preliminary X-ray analysis of the Thermoplasma acidophilum 20S proteasome in complex with protein substrates.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 64, 899-902.  
18006331 M.Hu, L.Qian, R.P.Briñas, E.S.Lymar, L.Kuznetsova, and J.F.Hainfeld (2008).
Gold nanoparticle-protein arrays improve resolution for cryo-electron microscopy.
  J Struct Biol, 161, 83-91.  
18832610 M.J.Pearce, J.Mintseris, J.Ferreyra, S.P.Gygi, and K.H.Darwin (2008).
Ubiquitin-like protein involved in the proteasome pathway of Mycobacterium tuberculosis.
  Science, 322, 1104-1107.  
18786393 P.C.Ramos, and R.J.Dohmen (2008).
PACemakers of proteasome core particle assembly.
  Structure, 16, 1296-1304.  
17277063 R.A.Festa, M.J.Pearce, and K.H.Darwin (2007).
Characterization of the proteasome accessory factor (paf) operon in Mycobacterium tuberculosis.
  J Bacteriol, 189, 3044-3050.  
17486317 R.De Mot, G.Schoofs, and I.Nagy (2007).
Proteome analysis of Streptomyces coelicolor mutants affected in the proteasome system reveals changes in stress-responsive proteins.
  Arch Microbiol, 188, 257-271.  
17587582 R.De Mot (2007).
Actinomycete-like proteasomes in a Gram-negative bacterium.
  Trends Microbiol, 15, 335-338.  
18059281 S.Gandotra, D.Schnappinger, M.Monteleone, W.Hillen, and S.Ehrt (2007).
In vivo gene silencing identifies the Mycobacterium tuberculosis proteasome as essential for the bacteria to persist in mice.
  Nat Med, 13, 1515-1520.  
16468985 G.Lin, G.Hu, C.Tsu, Y.Z.Kunes, H.Li, L.Dick, T.Parsons, P.Li, Z.Chen, P.Zwickl, N.Weich, and C.Nathan (2006).
Mycobacterium tuberculosis prcBA genes encode a gated proteasome with broad oligopeptide specificity.
  Mol Microbiol, 59, 1405-1416.  
17082771 M.J.Pearce, P.Arora, R.A.Festa, S.M.Butler-Wu, R.S.Gokhale, and K.H.Darwin (2006).
Identification of substrates of the Mycobacterium tuberculosis proteasome.
  EMBO J, 25, 5423-5432.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.

 

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