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PDBsum entry 2ren

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Hydrolase(acid proteinase) PDB id
2ren
Jmol
Contents
Protein chain
320 a.a. *
Ligands
NAG
* Residue conservation analysis
PDB id:
2ren
Name: Hydrolase(acid proteinase)
Title: Structure of recombinant human renin, a target for cardiovas active drugs, at 2.5 angstroms resolution
Structure: Renin. Chain: a. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606
Resolution:
2.50Å     R-factor:   0.217    
Authors: A.R.Sielecki,M.N.G.James
Key ref: A.R.Sielecki et al. (1989). Structure of recombinant human renin, a target for cardiovascular-active drugs, at 2.5 A resolution. Science, 243, 1346-1351. PubMed id: 2493678 DOI: 10.1126/science.2493678
Date:
05-Feb-92     Release date:   31-Jan-94    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00797  (RENI_HUMAN) -  Renin
Seq:
Struc:
406 a.a.
320 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.3.4.23.15  - Renin.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Cleaves Leu-|- bond in angiotensinogen to generate angiotensin I.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     proteolysis   1 term 
  Biochemical function     aspartic-type endopeptidase activity     1 term  

 

 
DOI no: 10.1126/science.2493678 Science 243:1346-1351 (1989)
PubMed id: 2493678  
 
 
Structure of recombinant human renin, a target for cardiovascular-active drugs, at 2.5 A resolution.
A.R.Sielecki, K.Hayakawa, M.Fujinaga, M.E.Murphy, M.Fraser, A.K.Muir, C.T.Carilli, J.A.Lewicki, J.D.Baxter, M.N.James.
 
  ABSTRACT  
 
The x-ray crystal structure of recombinant human renin has been determined. Molecular dynamics techniques that included crystallographic data as a restraint were used to improve an initial model based on porcine pepsinogen. The present agreement factor for data from 8.0 to 2.5 angstroms (A) is 0.236. Some of the surface loops are poorly determined, and these disordered regions border a 30 A wide solvent channel. Comparison of renin with other aspartyl proteinases shows that, although the structural cores and active sites are highly conserved, surface residues, some of which are critical for specificity, vary greatly (up to 10A). Knowledge of the actual structure, as opposed to the use of models based on related enzymes, should facilitate the design of renin inhibitors.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21376648 A.H.Al-Nadaf, and M.O.Taha (2011).
Discovery of new renin inhibitory leads via sequential pharmacophore modeling, QSAR analysis, in silico screening and in vitro evaluation.
  J Mol Graph Model, 29, 843-864.  
21036942 A.Michaud, D.Bur, O.Gribouval, L.Muller, X.Iturrioz, M.Clemessy, J.M.Gasc, M.C.Gubler, and P.Corvol (2011).
Loss-of-function point mutations associated with renal tubular dysgenesis provide insights about renin function and cellular trafficking.
  Hum Mol Genet, 20, 301-311.  
18237679 A.H.Gradman, and R.Kad (2008).
Renin inhibition in hypertension.
  J Am Coll Cardiol, 51, 519-528.  
18625162 B.K.Dockery, and J.D.Bisognano (2008).
Direct renin inhibition: an analysis of possible benefits.
  Curr Hypertens Rep, 10, 313-318.  
18340340 C.Jensen, P.Herold, and H.R.Brunner (2008).
Aliskiren: the first renin inhibitor for clinical treatment.
  Nat Rev Drug Discov, 7, 399-410.  
18764720 H.Siragy, J.Huang, and D.C.Lieb (2008).
The development of the direct renin inhibitor aliskiren: treating hypertension and beyond.
  Expert Opin Emerg Drugs, 13, 417-430.  
18398335 M.A.Schalekamp, F.H.Derkx, J.Deinum, and A.J.Danser (2008).
Newly developed renin and prorenin assays and the clinical evaluation of renin inhibitors.
  J Hypertens, 26, 928-937.  
  19183745 P.Verdecchia, F.Angeli, G.Mazzotta, G.Gentile, and G.Reboldi (2008).
The renin angiotensin system in the development of cardiovascular disease: role of aliskiren in risk reduction.
  Vasc Health Risk Manag, 4, 971-981.  
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.  
10074464 C.Oefner, A.Binggeli, V.Breu, D.Bur, J.P.Clozel, A.D'Arcy, A.Dorn, W.Fischli, F.Grüninger, R.Güller, G.Hirth, H.Märki, S.Mathews, M.M ller, R.G.Ridley, H.Stadler, E.Vieira, M.Wilhelm, F.Winkler, and W.Wostl (1999).
Renin inhibition by substituted piperidines: a novel paradigm for the inhibition of monomeric aspartic proteinases?
  Chem Biol, 6, 127-131.
PDB codes: 1pr7 1pr8
10598135 O.Valdenaire, V.Breu, T.Giller, D.Bur, and W.Fischli (1999).
Cloning and characterization of marmoset renin: comparison with human renin.
  J Cardiovasc Pharmacol, 34, 893-897.  
10427707 U.M.Nasir, F.Suzuki, T.Nagai, T.Nakagawa, and Y.Nakamura (1999).
Tyrosine-83 of human renin contributes to biphasic pH dependence of the renin-angiotensinogen reaction.
  Biosci Biotechnol Biochem, 63, 1143-1145.  
  9568890 A.R.Khan, and M.N.James (1998).
Molecular mechanisms for the conversion of zymogens to active proteolytic enzymes.
  Protein Sci, 7, 815-836.  
9761815 S.Karlsen, E.Hough, and R.L.Olsen (1998).
Structure and proposed amino-acid sequence of a pepsin from atlantic cod (Gadus morhua).
  Acta Crystallogr D Biol Crystallogr, 54, 32-46.
PDB code: 1am5
9532792 U.M.Nasir, K.Takahashi, T.Nagai, T.Nakagawa, F.Suzuki, and Y.Nakamura (1998).
Two peaks in pH dependence of renin-angiotensinogen reaction.
  Biosci Biotechnol Biochem, 62, 338-340.  
8778779 A.Beveridge (1996).
A theoretical study of torsional flexibility in the active site of aspartic proteinases: implications for catalysis.
  Proteins, 24, 322-334.  
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
  8976570 F.Grueninger-Leitch, A.D'Arcy, B.D'Arcy, and C.Chène (1996).
Deglycosylation of proteins for crystallization using recombinant fusion protein glycosidases.
  Protein Sci, 5, 2617-2622.  
8913621 G.Iliadis, B.Brzezinski, and G.Zundel (1996).
Aspartic proteinases: Fourier transform infrared spectroscopic studies of a model of the active side.
  Biophys J, 71, 2840-2847.  
9007691 S.OƂdziej, and J.Ciarkowski (1996).
Mechanism of action of aspartic proteinases: application of transition-state analogue theory.
  J Comput Aided Mol Des, 10, 583-588.  
7575336 J.Peters (1995).
Molecular basis of human hypertension: the role of angiotensin.
  Baillieres Clin Endocrinol Metab, 9, 657-678.  
8710824 S.Mosimann, R.Meleshko, and M.N.James (1995).
A critical assessment of comparative molecular modeling of tertiary structures of proteins.
  Proteins, 23, 301-317.  
  8282693 C.A.Conlin, K.Håkensson, A.Liljas, and C.G.Miller (1994).
Cloning and nucleotide sequence of the cyclic AMP receptor protein-regulated Salmonella typhimurium pepE gene and crystallization of its product, an alpha-aspartyl dipeptidase.
  J Bacteriol, 176, 166-172.  
7938177 J.M.Wood, F.Cumin, and J.Maibaum (1994).
Pharmacology of renin inhibitors and their application to the treatment of hypertension.
  Pharmacol Ther, 61, 325-344.  
8044845 N.P.Walker, R.V.Talanian, K.D.Brady, L.C.Dang, N.J.Bump, C.R.Ferenz, S.Franklin, T.Ghayur, M.C.Hackett, and L.D.Hammill (1994).
Crystal structure of the cysteine protease interleukin-1 beta-converting enzyme: a (p20/p10)2 homodimer.
  Cell, 78, 343-352.  
8035212 S.D.Rufino, and T.L.Blundell (1994).
Structure-based identification and clustering of protein families and superfamilies.
  J Comput Aided Mol Des, 8, 5.  
7824526 S.Pav, K.Lubbe, F.Dô, D.Lamarre, C.Pargellis, and L.Tong (1994).
Microtube batch protein crystallization: applications to human immunodeficiency virus type 2 (HIV-2) protease and human renin.
  Proteins, 20, 98.  
8393577 E.T.Baldwin, T.N.Bhat, S.Gulnik, M.V.Hosur, R.C.Sowder, R.E.Cachau, J.Collins, A.M.Silva, and J.W.Erickson (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.
PDB codes: 1lya 1lyb
8259000 S.S.Abdel-Meguid (1993).
Inhibitors of aspartyl proteinases.
  Med Res Rev, 13, 731-778.  
1603805 A.Sali, B.Veerapandian, J.B.Cooper, D.S.Moss, T.Hofmann, and T.L.Blundell (1992).
Domain flexibility in aspartic proteinases.
  Proteins, 12, 158-170.  
1603809 K.Suguna, E.A.Padlan, R.Bott, J.Boger, K.D.Parris, and D.R.Davies (1992).
Structures of complexes of rhizopuspepsin with pepstatin and other statine-containing inhibitors.
  Proteins, 13, 195-205.
PDB codes: 4apr 5apr 6apr
1528078 M.D.Walkinshaw (1992).
Protein targets for structure-based drug design.
  Med Res Rev, 12, 317-372.  
  1874000 C.Hutchins, and J.Greer (1991).
Comparative modeling of proteins in the design of novel renin inhibitors.
  Crit Rev Biochem Mol Biol, 26, 77.  
1781885 R.Edalji, T.F.Holzman, and E.J.Gubbins (1991).
Active prorenin: evidence for the formation of a conformational variant of recombinant human prorenin.
  J Protein Chem, 10, 403-406.  
1765127 R.J.Breckenridge (1991).
Molecular recognition: models for drug design.
  Experientia, 47, 1148-1161.  
1799412 T.F.Holzman, C.C.Chung, R.Edalji, D.A.Egan, M.Martin, E.J.Gubbins, G.A.Krafft, G.T.Wang, A.M.Thomas, and S.H.Rosenberg (1991).
Characterization of recombinant human renin: kinetics, pH-stability, and peptidomimetic inhibitor binding.
  J Protein Chem, 10, 553-563.  
2217165 C.Abad-Zapatero, T.J.Rydel, and J.Erickson (1990).
Revised 2.3 A structure of porcine pepsin: evidence for a flexible subdomain.
  Proteins, 8, 62-81.
PDB code: 3pep
2217166 G.L.Gilliland, E.L.Winborne, J.Nachman, and A.Wlodawer (1990).
The three-dimensional structure of recombinant bovine chymosin at 2.3 A resolution.
  Proteins, 8, 82.
PDB code: 1cms
2158092 I.T.Weber (1990).
Evaluation of homology modeling of HIV protease.
  Proteins, 7, 172-184.  
2153583 J.K.Rao, and A.Wlodawer (1990).
Is the pseudo-dyad in retroviral proteinase monomers structural or evolutionary?
  FEBS Lett, 260, 201-205.  
2085380 K.R.Acharya, D.I.Stuart, D.C.Phillips, and H.A.Scheraga (1990).
A critical evaluation of the predicted and X-ray structures of alpha-lactalbumin.
  J Protein Chem, 9, 549-563.  
2194793 M.A.Chidgey, and T.M.Harrison (1990).
Renin is sorted to the regulated secretory pathway in transfected PC12 cells by a mechanism which does not require expression of the pro-peptide.
  Eur J Biochem, 190, 139-144.  
1963533 T.F.Holzman, C.C.Chung, R.Edalji, D.A.Egan, E.J.Gubbins, A.Rueter, G.Howard, L.K.Yang, T.M.Pederson, and G.A.Krafft (1990).
Recombinant human prorenin from CHO cells: expression and purification.
  J Protein Chem, 9, 663-672.  
  2676515 A.Sali, B.Veerapandian, J.B.Cooper, S.I.Foundling, D.J.Hoover, and T.L.Blundell (1989).
High-resolution X-ray diffraction study of the complex between endothiapepsin and an oligopeptide inhibitor: the analysis of the inhibitor binding and description of the rigid body shift in the enzyme.
  EMBO J, 8, 2179-2188.
PDB code: 5er2
  2697983 J.D.Baxter, M.N.James, W.N.Chu, K.Duncan, M.A.Haidar, C.T.Carilli, and T.L.Reudelhuber (1989).
The molecular biology of human renin and its gene.
  Yale J Biol Med, 62, 493-501.  
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.