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Hydrolase/hydrolase inhibitor PDB id
1csb
Jmol
Contents
Protein chains
47 a.a. *
205 a.a. *
Ligands
EP0 ×2
Waters ×542
* Residue conservation analysis
PDB id:
1csb
Name: Hydrolase/hydrolase inhibitor
Title: Crystal structure of cathepsin b inhibited with ca030 at 2.1 resolution: a basis for the design of specific epoxysucciny inhibitors
Structure: Cathepsin b light chain. Chain: a, d. Cathepsin b heavy chain. Chain: b, e. Ec: 3.4.22.1
Source: Homo sapiens. Human. Organism_taxid: 9606. Organ: liver. Organelle: lysosome. Organelle: lysosome
Biol. unit: Trimer (from PQS)
Resolution:
2.00Å     R-factor:   0.194    
Authors: D.Turk,W.Bode
Key ref:
D.Turk et al. (1995). Crystal structure of cathepsin B inhibited with CA030 at 2.0-A resolution: A basis for the design of specific epoxysuccinyl inhibitors. Biochemistry, 34, 4791-4797. PubMed id: 7718586 DOI: 10.1021/bi00014a037
Date:
09-Dec-94     Release date:   03-Apr-96    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P07858  (CATB_HUMAN) -  Cathepsin B
Seq:
Struc: 		339 a.a.
47 a.a.
Protein chains
Pfam   ArchSchema ?
P07858  (CATB_HUMAN) -  Cathepsin B
Seq:
Struc: 		339 a.a.
205 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains A, B, D, E: E.C.3.4.22.1  - Cathepsin B.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Hydrolysis of proteins with broad specificity for peptide bonds. Preferentially cleaves -Arg-Arg-|-Xaa bonds in small molecule substrates (thus differing from cathepsin L). In addition to being an endopeptidase, shows peptidyl-dipeptidase activity, liberating C-terminal dipeptides.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     proteolysis   1 term 
  Biochemical function     cysteine-type peptidase activity     2 terms  

 

 
DOI no: 10.1021/bi00014a037 Biochemistry 34:4791-4797 (1995)
PubMed id: 7718586  
 
 
Crystal structure of cathepsin B inhibited with CA030 at 2.0-A resolution: A basis for the design of specific epoxysuccinyl inhibitors.
D.Turk, M.Podobnik, T.Popovic, N.Katunuma, W.Bode, R.Huber, V.Turk.
 
  ABSTRACT  
 
Crystals of cysteine protease human cathepsin B inhibited with CA030 (ethyl ester of epoxysuccinyl-Ile-Pro-OH) [Murata, M., et al. (1991) FEBS Lett. 280, were isomorphous to a previous published structure of cathepsin B [Musil, D., et al. (1991) EMBO J. 10, 2321-2330]. The crystal structure of the complex was refined at 2.0-A resolution to an R-value of 0.194. CA030 is well-defined in the electron density. The Ile-Pro-OH part of CA030 mimics a substrate P1' and P2' residues. The structure thus reveals for the first time a substratelike interaction in the S1' and S2' sites of a papain-like cysteine protease. The CA030 ethyl ester group occupies the S2 site. The structure confirms the role of residues His 110 and His 111 as the receptors of a peptidic substrate C-terminal carboxylic group. The structure suggests that an epoxysuccinyl fragment can be used to extend binding into primed and nonprimed substrate binding sites of a papain-like cysteine protease.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21321479 N.Katunuma (2011).
Structure-based development of specific inhibitors for individual cathepsins and their medical applications.
  Proc Jpn Acad Ser B Phys Biol Sci, 87, 29-39.  
20853148 X.Yao, J.Zhang, J.Sun, and B.Liu (2011).
Recombinant expression, characterization and expressional analysis of clam Meretrix meretrix cathepsin B, an enzyme involved in nutrient digestion.
  Mol Biol Rep, 38, 1861-1868.  
20980477 H.Kido, and K.Ishidoh (2010).
Nobuhiko Katunuma: an outstanding scientist in the field of proteolysis and warm-hearted 'Kendo Fighter' biochemist.
  J Biochem, 148, 527-531.  
21210971 M.G.Costa, P.R.Batista, C.S.Shida, C.H.Robert, P.M.Bisch, and P.G.Pascutti (2010).
How does heparin prevent the pH inactivation of cathepsin B? Allosteric mechanism elucidated by docking and molecular dynamics.
  BMC Genomics, 11, S5.  
20860624 M.Renko, U.Požgan, D.Majera, and D.Turk (2010).
Stefin A displaces the occluding loop of cathepsin B only by as much as required to bind to the active site cleft.
  FEBS J, 277, 4338-4345.  
19143833 J.R.Pungercar, D.Caglic, M.Sajid, M.Dolinar, O.Vasiljeva, U.Pozgan, D.Turk, M.Bogyo, V.Turk, and B.Turk (2009).
Autocatalytic processing of procathepsin B is triggered by proenzyme activity.
  FEBS J, 276, 660-668.  
19952439 T.Ishida (2009).
Structural studies of specific intermolecular interactions and self-aggregation of biomolecules and their application to drug design.
  Chem Pharm Bull (Tokyo), 57, 1309-1334.  
18959767 A.Tsuji, Y.Kikuchi, K.Ogawa, H.Saika, K.Yuasa, and M.Nagahama (2008).
Purification and characterization of cathepsin B-like cysteine protease from cotyledons of daikon radish, Raphanus sativus.
  FEBS J, 275, 5429-5443.  
17524981 A.M.Sadaghiani, S.H.Verhelst, V.Gocheva, K.Hill, E.Majerova, S.Stinson, J.A.Joyce, and M.Bogyo (2007).
Design, synthesis, and evaluation of in vivo potency and selectivity of epoxysuccinyl-based inhibitors of papain-family cysteine proteases.
  Chem Biol, 14, 499-511.  
15776409 S.H.Verhelst, and M.Bogyo (2005).
Solid-phase synthesis of double-headed epoxysuccinyl activity-based probes for selective targeting of papain family cysteine proteases.
  Chembiochem, 6, 824-827.  
15326171 Z.B.Mackey, T.C.O'Brien, D.C.Greenbaum, R.B.Blank, and J.H.McKerrow (2004).
A cathepsin B-like protease is required for host protein degradation in Trypanosoma brucei.
  J Biol Chem, 279, 48426-48433.  
14517908 A.Nayeem, S.Krystek, and T.Stouch (2003).
An assessment of protein-ligand binding site polarizability.
  Biopolymers, 70, 201-211.  
12887049 B.Turk, H.Fritz, and V.Turk (2003).
Vito Turk--30 years of research on cysteine proteases and their inhibitors.
  Biol Chem, 384, 833-836.  
12554931 D.Turk, and G.Guncar (2003).
Lysosomal cysteine proteases (cathepsins): promising drug targets.
  Acta Crystallogr D Biol Crystallogr, 59, 203-213.  
14665458 E.Villalobo, C.Moch, G.Fryd-Versavel, A.Fleury-Aubusson, and L.Morin (2003).
Cysteine proteases and cell differentiation: excystment of the ciliated protist Sterkiella histriomuscorum.
  Eukaryot Cell, 2, 1234-1245.  
12833545 M.Sulpizi, A.Laio, J.VandeVondele, A.Cattaneo, U.Rothlisberger, and P.Carloni (2003).
Reaction mechanism of caspases: insights from QM/MM Car-Parrinello simulations.
  Proteins, 52, 212-224.  
12668429 M.Sulpizi, U.Rothlisberger, and P.Carloni (2003).
Molecular dynamics studies of caspase-3.
  Biophys J, 84, 2207-2215.  
12887055 N.Katunuma, Y.Matsunaga, K.Himeno, and Y.Hayashi (2003).
Insights into the roles of cathepsins in antigen processing and presentation revealed by specific inhibitors.
  Biol Chem, 384, 883-890.  
14638781 R.H.Law, P.M.Smooker, J.A.Irving, D.Piedrafita, R.Ponting, N.J.Kennedy, J.C.Whisstock, R.N.Pike, and T.W.Spithill (2003).
Cloning and expression of the major secreted cathepsin B-like protein from juvenile Fasciola hepatica and analysis of immunogenicity following liver fluke infection.
  Infect Immun, 71, 6921-6932.  
  12401493 D.C.Greenbaum, W.D.Arnold, F.Lu, L.Hayrapetian, A.Baruch, J.Krumrine, S.Toba, K.Chehade, D.Brömme, I.D.Kuntz, and M.Bogyo (2002).
Small molecule affinity fingerprinting. A tool for enzyme family subclassification, target identification, and inhibitor design.
  Chem Biol, 9, 1085-1094.  
12437121 M.Montaser, G.Lalmanach, and L.Mach (2002).
CA-074, but not its methyl ester CA-074Me, is a selective inhibitor of cathepsin B within living cells.
  Biol Chem, 383, 1305-1308.  
11258881 C.Therrien, P.Lachance, T.Sulea, E.O.Purisima, H.Qi, E.Ziomek, A.Alvarez-Hernandez, W.R.Roush, and R.Ménard (2001).
Cathepsins X and B can be differentiated through their respective mono- and dipeptidyl carboxypeptidase activities.
  Biochemistry, 40, 2702-2711.  
11517928 D.Reverter, S.Strobl, C.Fernandez-Catalan, H.Sorimachi, K.Suzuki, and W.Bode (2001).
Structural basis for possible calcium-induced activation mechanisms of calpains.
  Biol Chem, 382, 753-766.  
11726493 D.Turk, V.Janjić, I.Stern, M.Podobnik, D.Lamba, S.W.Dahl, C.Lauritzen, J.Pedersen, V.Turk, and B.Turk (2001).
Structure of human dipeptidyl peptidase I (cathepsin C): exclusion domain added to an endopeptidase framework creates the machine for activation of granular serine proteases.
  EMBO J, 20, 6570-6582.
PDB code: 1k3b
11517939 R.Ménard, C.Therrien, P.Lachance, T.Sulea, H.Qo, A.D.Alvarez-Hernandez, and W.R.Roush (2001).
Cathepsins X and B display distinct activity profiles that can be exploited for inhibitor design.
  Biol Chem, 382, 839-845.  
11532926 V.Turk, B.Turk, and D.Turk (2001).
Lysosomal cysteine proteases: facts and opportunities.
  EMBO J, 20, 4629-4633.  
  10745011 G.Guncar, I.Klemencic, B.Turk, V.Turk, A.Karaoglanovic-Carmona, L.Juliano, and D.Turk (2000).
Crystal structure of cathepsin X: a flip-flop of the ring of His23 allows carboxy-monopeptidase and carboxy-dipeptidase activity of the protease.
  Structure, 8, 305-313.
PDB code: 1ef7
10662686 M.Bogyo, S.Verhelst, V.Bellingard-Dubouchaud, S.Toba, and D.Greenbaum (2000).
Selective targeting of lysosomal cysteine proteases with radiolabeled electrophilic substrate analogs.
  Chem Biol, 7, 27-38.  
10971478 R.Furmonaviciene, H.F.Sewell, and F.Shakib (2000).
Comparative molecular modelling identifies a common putative IgE epitope on cysteine protease allergens of diverse sources.
  Clin Exp Allergy, 30, 1307-1313.  
10350606 C.Czaplewski, Z.Grzonka, M.Jaskólski, F.Kasprzykowski, M.Kozak, E.Politowska, and J.Ciarkowski (1999).
Binding modes of a new epoxysuccinyl-peptide inhibitor of cysteine proteases. Where and how do cysteine proteases express their selectivity?
  Biochim Biophys Acta, 1431, 290-305.  
9914503 C.Serveau, G.Lalmanach, I.Hirata, J.Scharfstein, M.A.Juliano, and F.Gauthier (1999).
Discrimination of cruzipain, the major cysteine proteinase of Trypanosoma cruzi, and mammalian cathepsins B and L, by a pH-inducible fluorogenic substrate of trypanosomal cysteine proteinases.
  Eur J Biochem, 259, 275-280.  
10384960 E.Krepela, J.Procházka, and B.Kárová (1999).
Regulation of cathepsin B activity by cysteine and related thiols.
  Biol Chem, 380, 541-551.  
10383408 J.A.Schmid, L.Mach, E.Paschke, and J.Glössl (1999).
Accumulation of sialic acid in endocytic compartments interferes with the formation of mature lysosomes. Impaired proteolytic processing of cathepsin B in fibroblasts of patients with lysosomal sialic acid storage disease.
  J Biol Chem, 274, 19063-19071.  
10380357 K.Matsumoto, K.Mizoue, K.Kitamura, W.C.Tse, C.P.Huber, and T.Ishida (1999).
Structural basis of inhibition of cysteine proteases by E-64 and its derivatives.
  Biopolymers, 51, 99.  
10410800 M.E.McGrath (1999).
The lysosomal cysteine proteases.
  Annu Rev Biophys Biomol Struct, 28, 181-204.  
10470376 N.Katunuma, A.Matsui, T.Kakegawa, E.Murata, T.Asao, and Y.Ohba (1999).
Study of the functional share of lysosomal cathepsins by the development of specific inhibitors.
  Adv Enzyme Regul, 39, 247-260.  
10380356 T.Schirmeister (1999).
Inhibition of cysteine proteases by peptides containing aziridine-2,3-dicarboxylic acid building blocks.
  Biopolymers, 51, 87-97.  
  9493267 G.Guncar, M.Podobnik, J.Pungercar, B.Strukelj, V.Turk, and D.Turk (1998).
Crystal structure of porcine cathepsin H determined at 2.1 A resolution: location of the mini-chain C-terminal carboxyl group defines cathepsin H aminopeptidase function.
  Structure, 6, 51-61.
PDB code: 8pch
  9655332 M.E.McGrath, J.T.Palmer, D.Brömme, and J.R.Somoza (1998).
Crystal structure of human cathepsin S.
  Protein Sci, 7, 1294-1302.  
9762356 N.Katunuma, Y.Matsunaga, A.Matsui, H.Kakegawa, K.Endo, T.Inubushi, T.Saibara, Y.Ohba, and T.Kakiuchi (1998).
Novel physiological functions of cathepsins B and L on antigen processing and osteoclastic bone resorption.
  Adv Enzyme Regul, 38, 235-251.  
8995421 C.Illy, O.Quraishi, J.Wang, E.Purisima, T.Vernet, and J.S.Mort (1997).
Role of the occluding loop in cathepsin B activity.
  J Biol Chem, 272, 1197-1202.  
9033587 M.E.McGrath, J.L.Klaus, M.G.Barnes, and D.Brömme (1997).
Crystal structure of human cathepsin K complexed with a potent inhibitor.
  Nat Struct Biol, 4, 105-109.
PDB code: 1mem
9354234 N.Schaschke, I.Assfalg-Machleidt, W.Machleidt, D.Turk, and L.Moroder (1997).
E-64 analogues as inhibitors of cathepsin B. On the role of the absolute configuration of the epoxysuccinyl group.
  Bioorg Med Chem, 5, 1789-1797.  
  9260273 S.A.Gillmor, C.S.Craik, and R.J.Fletterick (1997).
Structural determinants of specificity in the cysteine protease cruzain.
  Protein Sci, 6, 1603-1611.
PDB codes: 1aim 2aim
9233788 S.C.Johnston, C.N.Larsen, W.J.Cook, K.D.Wilkinson, and C.P.Hill (1997).
Crystal structure of a deubiquitinating enzyme (human UCH-L3) at 1.8 A resolution.
  EMBO J, 16, 3787-3796.
PDB code: 1uch
  9165062 W.Baumeister, Z.Cejka, M.Kania, and E.Seemüller (1997).
The proteasome: a macromolecular assembly designed to confine proteolysis to a nanocompartment.
  Biol Chem, 378, 121-130.  
8672429 D.Brömme, P.R.Bonneau, E.Purisima, P.Lachance, S.Hajnik, D.Y.Thomas, and A.C.Storer (1996).
Contribution to activity of histidine-aromatic, amide-aromatic, and aromatic-aromatic interactions in the extended catalytic site of cysteine proteinases.
  Biochemistry, 35, 3970-3979.  
  8740363 M.Cygler, J.Sivaraman, P.Grochulski, R.Coulombe, A.C.Storer, and J.S.Mort (1996).
Structure of rat procathepsin B: model for inhibition of cysteine protease activity by the proregion.
  Structure, 4, 405-416.
PDB code: 1mir
  8939744 M.R.Groves, M.A.Taylor, M.Scott, N.J.Cummings, R.W.Pickersgill, and J.A.Jenkins (1996).
The prosequence of procaricain forms an alpha-helical domain that prevents access to the substrate-binding cleft.
  Structure, 4, 1193-1203.
PDB code: 1pci
  8896443 R.Coulombe, P.Grochulski, J.Sivaraman, R.Ménard, J.S.Mort, and M.Cygler (1996).
Structure of human procathepsin L reveals the molecular basis of inhibition by the prosegment.
  EMBO J, 15, 5492-5503.
PDB code: 1cjl
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 code is shown on the right.