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PDBsum entry 1lya

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protein ligands Protein-protein interface(s) links
Lysosomal aspartic protease PDB id
1lya
Jmol
Contents
Protein chains
97 a.a. *
241 a.a. *
Ligands
NAG-NAG-BMA-MAN ×2
NAG ×2
Waters ×138
* Residue conservation analysis
PDB id:
1lya
Name: Lysosomal aspartic protease
Title: Crystal structures of native and inhibited forms of human ca implications for lysosomal targeting and drug design
Structure: Cathepsin d. Chain: a, c. Cathepsin d. Chain: b, d. Ec: 3.4.23.5
Source: Homo sapiens. Human. Organism_taxid: 9606. Organ: liver. Tissue: liver. Tissue: liver
Biol. unit: Hetero-Dimer (from PQS)
Resolution:
2.50Å     R-factor:   0.188    
Authors: E.T.Baldwin,T.N.Bhat,S.Gulnik,J.W.Erickson
Key ref: E.T.Baldwin et al. (1993). Crystal structures of native and inhibited forms of human cathepsin D: implications for lysosomal targeting and drug design. Proc Natl Acad Sci U S A, 90, 6796-6800. PubMed id: 8393577 DOI: 10.1073/pnas.90.14.6796
Date:
22-Apr-93     Release date:   31-Jan-94    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P07339  (CATD_HUMAN) -  Cathepsin D
Seq:
Struc:
412 a.a.
97 a.a.
Protein chains
Pfam   ArchSchema ?
P07339  (CATD_HUMAN) -  Cathepsin D
Seq:
Struc:
412 a.a.
241 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains A, B, C, D: E.C.3.4.23.5  - Cathepsin D.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Specificity similar to, but narrower than, that of pepsin A. Does not cleave the 4-Gln-|-His-5 bond in B chain of insulin.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     proteolysis   1 term 
  Biochemical function     aspartic-type endopeptidase activity     1 term  

 

 
DOI no: 10.1073/pnas.90.14.6796 Proc Natl Acad Sci U S A 90:6796-6800 (1993)
PubMed id: 8393577  
 
 
Crystal structures of native and inhibited forms of human cathepsin D: implications for lysosomal targeting and drug design.
E.T.Baldwin, T.N.Bhat, S.Gulnik, M.V.Hosur, R.C.Sowder, R.E.Cachau, J.Collins, A.M.Silva, J.W.Erickson.
 
  ABSTRACT  
 
Cathepsin D (EC 3.4.23.5) is a lysosomal protease suspected to play important roles in protein catabolism, antigen processing, degenerative diseases, and breast cancer progression. Determination of the crystal structures of cathepsin D and a complex with pepstatin at 2.5 A resolution provides insights into inhibitor binding and lysosomal targeting for this two-chain, N-glycosylated aspartic protease. Comparison with the structures of a complex of pepstatin bound to rhizopuspepsin and with a human renin-inhibitor complex revealed differences in subsite structures and inhibitor-enzyme interactions that are consistent with affinity differences and structure-activity relationships and suggest strategies for fine-tuning the specificity of cathepsin D inhibitors. Mutagenesis studies have identified a phosphotransferase recognition region that is required for oligosaccharide phosphorylation but is 32 A distant from the N-domain glycosylation site at Asn-70. Electron density for the crystal structure of cathepsin D indicated the presence of an N-linked oligosaccharide that extends from Asn-70 toward Lys-203, which is a key component of the phosphotransferase recognition region, and thus provides a structural explanation for how the phosphotransferase can recognize apparently distant sites on the protein surface.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20740315 P.Manoharan, R.S.Vijayan, and N.Ghoshal (2010).
Rationalizing fragment based drug discovery for BACE1: insights from FB-QSAR, FB-QSSR, multi objective (MO-QSPR) and MIF studies.
  J Comput Aided Mol Des, 24, 843-864.  
19802014 P.Nirdé, D.Derocq, M.Maynadier, M.Chambon, I.Basile, M.Gary-Bobo, and M.Garcia (2010).
Heat shock cognate 70 protein secretion as a new growth arrest signal for cancer cells.
  Oncogene, 29, 117-127.  
19995700 A.Minarowska, A.Karwowska, and M.Gacko (2009).
Quantitative determination and localization of cathepsin D and its inhibitors.
  Folia Histochem Cytobiol, 47, 153-177.  
19715320 J.C.Kwan, E.A.Eksioglu, C.Liu, V.J.Paul, and H.Luesch (2009).
Grassystatins A-C from marine cyanobacteria, potent cathepsin E inhibitors that reduce antigen presentation.
  J Med Chem, 52, 5732-5747.  
19380510 M.S.Pearson, J.M.Bethony, D.A.Pickering, L.M.de Oliveira, A.Jariwala, H.Santiago, A.P.Miles, B.Zhan, D.Jiang, N.Ranjit, J.Mulvenna, L.Tribolet, J.Plieskatt, T.Smith, M.E.Bottazzi, K.Jones, B.Keegan, P.J.Hotez, and A.Loukas (2009).
An enzymatically inactivated hemoglobinase from Necator americanus induces neutralizing antibodies against multiple hookworm species and protects dogs against heterologous hookworm infection.
  FASEB J, 23, 3007-3019.  
  18296260 A.Minarowska, M.Gacko, A.Karwowska, and Å..Minarowski (2008).
Human cathepsin D.
  Folia Histochem Cytobiol, 46, 23-38.  
18498103 D.C.Bas, D.M.Rogers, and J.H.Jensen (2008).
Very fast prediction and rationalization of pKa values for protein-ligand complexes.
  Proteins, 73, 765-783.  
19088746 L.D.Rumsh, A.G.Mikhailova, I.V.Mikhura, I.A.Prudchenko, L.D.Chikin, I.I.Mikhaleva, E.N.Kaliberda, N.I.Dergousova, E.E.Mel'nikov, and A.A.Formanovskii (2008).
[Selective Inhibitors of Plasmepsin II from Plasmodium falciparum Based on Pepstatin.]
  Bioorg Khim, 34, 739-746.  
18396408 P.Benes, V.Vetvicka, and M.Fusek (2008).
Cathepsin D--many functions of one aspartic protease.
  Crit Rev Oncol Hematol, 68, 12-28.  
18384529 W.Sherman, and B.Tidor (2008).
Novel method for probing the specificity binding profile of ligands: applications to HIV protease.
  Chem Biol Drug Des, 71, 387-407.  
17447722 C.L.Parr, R.A.Keates, B.C.Bryksa, M.Ogawa, and R.Y.Yada (2007).
The structure and function of Saccharomyces cerevisiae proteinase A.
  Yeast, 24, 467-480.  
17549046 S.Ekins, J.Mestres, and B.Testa (2007).
In silico pharmacology for drug discovery: applications to targets and beyond.
  Br J Pharmacol, 152, 21-37.  
16307463 C.Binkert, M.Frigerio, A.Jones, S.Meyer, C.Pesenti, L.Prade, F.Viani, and M.Zanda (2006).
Replacement of isobutyl by trifluoromethyl in pepstatin A selectively affects inhibition of aspartic proteinases.
  Chembiochem, 7, 181-186.  
16046058 E.Liaudet-Coopman, M.Beaujouin, D.Derocq, M.Garcia, M.Glondu-Lassis, V.Laurent-Matha, C.Prébois, H.Rochefort, and F.Vignon (2006).
Cathepsin D: newly discovered functions of a long-standing aspartic protease in cancer and apoptosis.
  Cancer Lett, 237, 167-179.  
16892342 E.Specker, J.Böttcher, S.Brass, A.Heine, H.Lilie, A.Schoop, G.Müller, N.Griebenow, and G.Klebe (2006).
Unexpected novel binding mode of pyrrolidine-based aspartyl protease inhibitors: design, synthesis and crystal structure in complex with HIV protease.
  ChemMedChem, 1, 106-117.  
16838300 K.Ersmark, B.Samuelsson, and A.Hallberg (2006).
Plasmepsins as potential targets for new antimalarial therapy.
  Med Res Rev, 26, 626-666.  
16685649 R.Steinfeld, K.Reinhardt, K.Schreiber, M.Hillebrand, R.Kraetzner, W.Bruck, P.Saftig, and J.Gartner (2006).
Cathepsin D deficiency is associated with a human neurodegenerative disorder.
  Am J Hum Genet, 78, 988-998.  
16640331 S.Zhang, A.Golbraikh, and A.Tropsha (2006).
Development of quantitative structure-binding affinity relationship models based on novel geometrical chemical descriptors of the protein-ligand interfaces.
  J Med Chem, 49, 2713-2724.  
15899696 C.R.Caffrey, L.Placha, C.Barinka, M.Hradilek, J.Dostál, M.Sajid, J.H.McKerrow, P.Majer, J.Konvalinka, and J.Vondrásek (2005).
Homology modeling and SAR analysis of Schistosoma japonicum cathepsin D (SjCD) with statin inhibitors identify a unique active site steric barrier with potential for the design of specific inhibitors.
  Biol Chem, 386, 339-349.  
15822136 E.Specker, J.Böttcher, H.Lilie, A.Heine, A.Schoop, G.Müller, N.Griebenow, and G.Klebe (2005).
An old target revisited: two new privileged skeletons and an unexpected binding mode for HIV-protease inhibitors.
  Angew Chem Int Ed Engl, 44, 3140-3144.
PDB codes: 1xl2 1xl5
16313175 N.E.Goldfarb, M.T.Lam, A.K.Bose, A.M.Patel, A.J.Duckworth, and B.M.Dunn (2005).
Electrostatic switches that mediate the pH-dependent conformational change of "short" recombinant human pseudocathepsin D.
  Biochemistry, 44, 15725-15733.  
15229889 E.Alexov (2004).
Calculating proton uptake/release and binding free energy taking into account ionization and conformation changes induced by protein-inhibitor association: application to plasmepsin, cathepsin D and endothiapepsin-pepstatin complexes.
  Proteins, 56, 572-584.  
15287985 M.Mohamadzadeh, H.Mohamadzadeh, M.Brammer, K.Sestak, and R.B.Luftig (2004).
Identification of proteases employed by dendritic cells in the processing of protein purified derivative (PPD).
  J Immune Based Ther Vaccines, 2, 8.  
12575995 K.Gunasekaran, C.J.Tsai, S.Kumar, D.Zanuy, and R.Nussinov (2003).
Extended disordered proteins: targeting function with less scaffold.
  Trends Biochem Sci, 28, 81-85.  
11913384 A.Cheng, D.J.Diller, S.L.Dixon, W.J.Egan, G.Lauri, and K.M.Merz (2002).
Computation of the physio-chemical properties and data mining of large molecular collections.
  J Comput Chem, 23, 172-183.  
11790828 B.Ma, M.Shatsky, H.J.Wolfson, and R.Nussinov (2002).
Multiple diverse ligands binding at a single protein site: a matter of pre-existing populations.
  Protein Sci, 11, 184-197.  
11679720 F.Canduri, L.G.Teodoro, V.Fadel, C.C.Lorenzi, V.Hial, R.A.Gomes, J.R.Neto, and W.F.de Azevedo (2001).
Structure of human uropepsin at 2.45 A resolution.
  Acta Crystallogr D Biol Crystallogr, 57, 1560-1570.
PDB code: 1flh
11714911 N.S.Andreeva, and L.D.Rumsh (2001).
Analysis of crystal structures of aspartic proteinases: on the role of amino acid residues adjacent to the catalytic site of pepsin-like enzymes.
  Protein Sci, 10, 2439-2450.  
11418762 S.W.Cho, N.Kim, M.U.Choi, and W.Shin (2001).
Structure of aspergillopepsin I from Aspergillus phoenicis: variations of the S1'-S2 subsite in aspartic proteinases.
  Acta Crystallogr D Biol Crystallogr, 57, 948-956.
PDB code: 1ibq
  11106168 C.A.Galea, B.P.Dalrymple, R.Kuypers, and R.Blakeley (2000).
Modification of the substrate specificity of porcine pepsin for the enzymatic production of bovine hide gelatin.
  Protein Sci, 9, 1947-1959.  
11074266 D.R.Howlett, D.L.Simmons, C.Dingwall, and G.Christie (2000).
In search of an enzyme: the beta-secretase of Alzheimer's disease is an aspartic proteinase.
  Trends Neurosci, 23, 565-570.  
10666618 J.B.Cooper, and D.A.Myles (2000).
A preliminary neutron Laue diffraction study of the aspartic proteinase endothiapepsin.
  Acta Crystallogr D Biol Crystallogr, 56, 246-248.  
10931940 M.Farzan, C.E.Schnitzler, N.Vasilieva, D.Leung, and H.Choe (2000).
BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein.
  Proc Natl Acad Sci U S A, 97, 9712-9717.  
  10850809 Q.N.Cao, M.Stubbs, K.Q.Ngo, M.Ward, A.Cunningham, E.F.Pai, G.C.Tu, and T.Hofmann (2000).
Penicillopepsin-JT2, a recombinant enzyme from Penicillium janthinellum and the contribution of a hydrogen bond in subsite S3 to k(cat).
  Protein Sci, 9, 991.  
10861751 V.Vetvicka, J.Vetvickova, and M.Fusek (2000).
Role of procathepsin D activation peptide in prostate cancer growth.
  Prostate, 44, 1-7.  
10209280 C.Capasso, W.E.Lees, A.Capasso, R.Scudiero, V.Carginale, P.Kille, J.Kay, and E.Parisi (1999).
Cathepsin D from the liver of the antarctic icefish Chionodraco hamatus exhibits unusual activity and stability at high temperatures1.
  Biochim Biophys Acta, 1431, 64-73.  
  10548045 J.Westling, P.Cipullo, S.H.Hung, H.Saft, J.B.Dame, and B.M.Dunn (1999).
Active site specificity of plasmepsin II.
  Protein Sci, 8, 2001-2009.  
9783744 A.Y.Lee, S.V.Gulnik, and J.W.Erickson (1998).
Conformational switching in an aspartic proteinase.
  Nat Struct Biol, 5, 866-871.
PDB code: 1lyw
  9514263 B.M.Beyer, and B.M.Dunn (1998).
Prime region subsite specificity characterization of human cathepsin D: the dominant role of position 128.
  Protein Sci, 7, 88-95.  
9363769 D.Arnold, W.Keilholz, H.Schild, T.Dumrese, S.Stevanović, and H.G.Rammensee (1997).
Substrate specificity of cathepsins D and E determined by N-terminal and C-terminal sequencing of peptide pools.
  Eur J Biochem, 249, 171-179.  
  9377485 D.Arnold, W.Keilholz, H.Schild, T.Dumrese, S.Stevanović, and H.G.Rammensee (1997).
Evolutionary conserved cathepsin E substrate specificity as defined by N-terminal and C-terminal sequencing of peptide pools.
  Biol Chem, 378, 883-891.  
  9232647 P.Majer, J.R.Collins, S.V.Gulnik, and J.W.Erickson (1997).
Structure-based subsite specificity mapping of human cathepsin D using statine-based inhibitors.
  Protein Sci, 6, 1458-1466.  
9362483 R.Tikkanen, M.Peltola, C.Oinonen, J.Rouvinen, and L.Peltonen (1997).
Several cooperating binding sites mediate the interaction of a lysosomal enzyme with phosphotransferase.
  EMBO J, 16, 6684-6693.  
8816746 A.M.Silva, A.Y.Lee, S.V.Gulnik, P.Maier, J.Collins, T.N.Bhat, P.J.Collins, R.E.Cachau, K.E.Luker, I.Y.Gluzman, S.E.Francis, A.Oksman, D.E.Goldberg, and J.W.Erickson (1996).
Structure and inhibition of plasmepsin II, a hemoglobin-degrading enzyme from Plasmodium falciparum.
  Proc Natl Acad Sci U S A, 93, 10034-10039.
PDB code: 1sme
8768899 D.F.Wyss, and G.Wagner (1996).
The structural role of sugars in glycoproteins.
  Curr Opin Biotechnol, 7, 409-416.  
7567964 C.Rao-Naik, K.Guruprasad, B.Batley, S.Rapundalo, J.Hill, T.Blundell, J.Kay, and B.M.Dunn (1995).
Exploring the binding preferences/specificity in the active site of human cathepsin E.
  Proteins, 22, 168-181.  
8591035 G.Rudenko, E.Bonten, A.d'Azzo, and W.G.Hol (1995).
Three-dimensional structure of the human 'protective protein': structure of the precursor form suggests a complex activation mechanism.
  Structure, 3, 1249-1259.
PDB code: 1ivy
  7663352 M.Fujinaga, M.M.Chernaia, N.I.Tarasova, S.C.Mosimann, and M.N.James (1995).
Crystal structure of human pepsin and its complex with pepstatin.
  Protein Sci, 4, 960-972.
PDB codes: 1psn 1pso
8591036 S.M.Cutfield, E.J.Dodson, B.F.Anderson, P.C.Moody, C.J.Marshall, P.A.Sullivan, and J.F.Cutfield (1995).
The crystal structure of a major secreted aspartic proteinase from Candida albicans in complexes with two inhibitors.
  Structure, 3, 1261-1271.
PDB code: 1eag
  8061605 K.Baumann, G.Zanotti, and H.Faulstich (1994).
A beta-turn in alpha-amanitin is the most important structural feature for binding to RNA polymerase II and three monoclonal antibodies.
  Protein Sci, 3, 750-756.  
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.