PDBsum entry 1pr8

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Hydrolase PDB id
Protein chain
336 a.a.
PDB id:
Name: Hydrolase
Title: Human renin complexed with a substituted piperidine
Structure: Renin. Chain: a. Engineered: yes
Source: Homo sapiens. Human. Expressed in: cho cells
2.90Å     R-factor:   0.160    
Authors: C.Oefner,A.D'Arcy
Key ref: C.Oefner et al. (1999). Renin inhibition by substituted piperidines: a novel paradigm for the inhibition of monomeric aspartic proteinases? Chem Biol, 6, 127-131. PubMed id: 10074464
20-Jun-03     Release date:   08-Jul-03    
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Protein chain
No UniProt id for this chain
Struc: 336 a.a.
Key:    Secondary structure


Chem Biol 6:127-131 (1999)
PubMed id: 10074464  
Renin inhibition by substituted piperidines: a novel paradigm for the inhibition of monomeric aspartic proteinases?
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, W.Wostl.
BACKGROUND: The aspartic proteinase renin catalyses the first and rate-limiting step in the conversion of angiotensinogen to the hormone angiotensin II, and therefore plays an important physiological role in the regulation of blood pressure. Numerous potent peptidomimetic inhibitors of this important drug target have been developed, but none of these compounds have progressed past clinical phase II trials. Limited oral bioavailability or excessive production costs have prevented these inhibitors from becoming new antihypertensive drugs. We were interested in developing new nonpeptidomimetic renin inhibitors. RESULTS: High-throughput screening of the Roche compound library identified a simple 3, 4-disubstituted piperidine lead compound. We determined the crystal structures of recombinant human renin complexed with two representatives of this new class. Binding of these substituted piperidine derivatives is accompanied by major induced-fit adaptations around the enzyme's active site. CONCLUSIONS: The efficient optimisation of the piperidine inhibitors was facilitated by structural analysis of the renin active site in two renin-inhibitor complexes (some of the piperidine derivatives have picomolar affinities for renin). These structural changes provide the basis for a novel paradigm for inhibition of monomeric aspartic proteinases.

Literature references that cite this PDB file's key reference Google scholar

  PubMed id Reference
21429746 R.Aspiotis, A.Chen, E.Cauchon, D.Dubé, J.P.Falgueyret, S.Gagné, M.Gallant, E.L.Grimm, R.Houle, H.Juteau, P.Lacombe, S.Laliberté, J.F.Lévesque, D.MacDonald, D.McKay, M.D.Percival, P.Roy, S.M.Soisson, and T.Wu (2011).
The discovery and synthesis of potent zwitterionic inhibitors of renin.
  Bioorg Med Chem Lett, 21, 2430-2436.  
20237659 J.F.Bower, J.Rujirawanich, and T.Gallagher (2010).
N-heterocycle construction via cyclic sulfamidates. Applications in synthesis.
  Org Biomol Chem, 8, 1505-1519.  
19285084 P.Bhaumik, H.Xiao, C.L.Parr, Y.Kiso, A.Gustchina, R.Y.Yada, and A.Wlodawer (2009).
Crystal structures of the histo-aspartic protease (HAP) from Plasmodium falciparum.
  J Mol Biol, 388, 520-540.
PDB codes: 3fns 3fnt 3fnu
17918177 M.Zürcher, T.Gottschalk, S.Meyer, D.Bur, and F.Diederich (2008).
Exploring the flap pocket of the antimalarial target plasmepsin II: the "55 % rule" applied to enzymes.
  ChemMedChem, 3, 237-240.  
18752222 T.Luksch, N.S.Chan, S.Brass, C.A.Sotriffer, G.Klebe, and W.E.Diederich (2008).
Computer-aided design and synthesis of nonpeptidic plasmepsin II and IV inhibitors.
  ChemMedChem, 3, 1323-1336.  
17392964 J.F.Bower, T.Riis-Johannessen, P.Szeto, A.J.Whitehead, and T.Gallagher (2007).
Stereospecific construction of substituted piperidines. Synthesis of (-)-paroxetine and (+)-laccarin.
  Chem Commun (Camb), (), 728-730.  
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.  
17091526 C.Boss, O.Corminboeuf, C.Grisostomi, S.Meyer, A.F.Jones, L.Prade, C.Binkert, W.Fischli, T.Weller, and D.Bur (2006).
Achiral, cheap, and potent inhibitors of Plasmepsins I, II, and IV.
  ChemMedChem, 1, 1341-1345.
PDB codes: 2igx 2igy
16838300 K.Ersmark, B.Samuelsson, and A.Hallberg (2006).
Plasmepsins as potential targets for new antimalarial therapy.
  Med Res Rev, 26, 626-666.  
16895485 T.J.Winterburn, D.M.Wyatt, L.H.Phylip, C.Berry, D.Bur, and J.Kay (2006).
Adaptation of the behaviour of an aspartic proteinase inhibitor by relocation of a lysine residue by one helical turn.
  Biol Chem, 387, 1139-1142.  
16216580 A.A.Gorfe, and A.Caflisch (2005).
Functional plasticity in the substrate binding site of beta-secretase.
  Structure, 13, 1487-1498.  
15840589 L.Prade, A.F.Jones, C.Boss, S.Richard-Bildstein, S.Meyer, C.Binkert, and D.Bur (2005).
X-ray structure of plasmepsin II complexed with a potent achiral inhibitor.
  J Biol Chem, 280, 23837-23843.
PDB code: 2bju
16204988 R.Paruszewski, P.Jaworski, M.Bodnar, J.Dudkiewicz-WilczyƄska, and I.Roman (2005).
New renin inhibitors containing pseudodipeptidic units in P3-P2 and P1-P1' positions.
  Chem Pharm Bull (Tokyo), 53, 1305-1309.  
15582452 W.L.Cody, D.D.Holsworth, N.A.Powell, M.Jalaie, E.Zhang, W.Wang, B.Samas, J.Bryant, R.Ostroski, M.J.Ryan, and J.J.Edmunds (2005).
The discovery and preparation of disubstituted novel amino-aryl-piperidine-based renin inhibitors.
  Bioorg Med Chem, 13, 59-68.  
14997208 L.Juillerat-Jeanneret, J.Celerier, C.Chapuis Bernasconi, G.Nguyen, W.Wostl, H.P.Maerki, R.C.Janzer, P.Corvol, and J.M.Gasc (2004).
Renin and angiotensinogen expression and functions in growth and apoptosis of human glioblastoma.
  Br J Cancer, 90, 1059-1068.  
12458195 L.Toulokhonova, W.J.Metzler, M.R.Witmer, R.A.Copeland, and J.Marcinkeviciene (2003).
Kinetic studies on beta-site amyloid precursor protein-cleaving enzyme (BACE). Confirmation of an iso mechanism.
  J Biol Chem, 278, 4582-4589.  
12838268 S.J.Teague (2003).
Implications of protein flexibility for drug discovery.
  Nat Rev Drug Discov, 2, 527-541.  
12325161 D.H.Rich, M.G.Bursavich, and M.A.Estiarte (2002).
Discovery of nonpeptide, peptidomimetic peptidase inhibitors that target alternate enzyme active site conformations.
  Biopolymers, 66, 115-125.  
12325160 E.Bianchi, and A.Pessi (2002).
Inhibiting viral proteases: challenges and opportunities.
  Biopolymers, 66, 101-114.  
12029090 J.Marcinkeviciene, L.M.Kopcho, T.Yang, R.A.Copeland, B.M.Glass, A.P.Combs, N.Falahatpisheh, and L.Thompson (2002).
Novel inhibition of porcine pepsin by a substituted piperidine. Preference for one of the enzyme conformers.
  J Biol Chem, 277, 28677-28682.  
11400666 G.Klebe (2001).
[Molecular modeling in the battle against AIDS. Drugs design in the development of substrate-like HIV protease inhibitors]
  Pharm Unserer Zeit, 30, 194-201.  
10607668 N.K.Bernstein, and M.N.James (1999).
Novel ways to prevent proteolysis - prophytepsin and proplasmepsin II.
  Curr Opin Struct Biol, 9, 684-689.  
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.  
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.