PDBsum entry 2v12

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Hydrolase PDB id
Protein chain
334 a.a. *
C39 ×2
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Crystal structure of renin with inhibitor 8
Structure: Renin. Chain: c, o. Synonym: angiotensinogenase. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_cell_line: cho cells
3.20Å     R-factor:   0.236    
Authors: J.Rahuel,V.Rasetti,J.Maibaum,H.Rueger,R.Goschke,N.C.Cohen, S.Stutz,F.Cumin,W.Fuhrer,J.M.Wood,M.G.Grutter
Key ref:
J.Rahuel et al. (2000). Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin. Chem Biol, 7, 493-504. PubMed id: 10903938 DOI: 10.1016/S1074-5521(00)00134-4
21-May-07     Release date:   03-Jul-07    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P00797  (RENI_HUMAN) -  Renin
406 a.a.
334 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - 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: 10.1016/S1074-5521(00)00134-4 Chem Biol 7:493-504 (2000)
PubMed id: 10903938  
Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin.
J.Rahuel, V.Rasetti, J.Maibaum, H.Rüeger, R.Göschke, N.C.Cohen, S.Stutz, F.Cumin, W.Fuhrer, J.M.Wood, M.G.Grütter.
BACKGROUND: The aspartic proteinase renin plays an important physiological role in the regulation of blood pressure. It catalyses the first step in the conversion of angiotensinogen to the hormone angiotensin II. In the past, potent peptide inhibitors of renin have been developed, but none of these compounds has made it to the end of clinical trials. Our primary aim was to develop novel nonpeptide inhibitors. Based on the available structural information concerning renin-substrate interactions, we synthesized inhibitors in which the peptide portion was replaced by lipophilic moieties that interact with the large hydrophobic S1/S3-binding pocket in renin. RESULTS: Crystal structure analysis of renin-inhibitor complexes combined with computational methods were employed in the medicinal-chemistry optimisation process. Structure analysis revealed that the newly designed inhibitors bind as predicted to the S1/S3 pocket. In addition, however, these compounds interact with a hitherto unrecognised large, distinct, sub-pocket of the enzyme that extends from the S3-binding site towards the hydrophobic core of the enzyme. Binding to this S3(sp) sub-pocket was essential for high binding affinity. This unprecedented binding mode guided the drug-design process in which the mostly hydrophobic interactions within subsite S3(sp) were optimised. CONCLUSIONS: Our design approach led to compounds with high in vitro affinity and specificity for renin, favourable bioavailability and excellent oral efficacy in lowering blood pressure in primates. These renin inhibitors are therefore potential therapeutic agents for the treatment of hypertension and related cardiovascular diseases.
  Selected figure(s)  
Figure 5.
Figure 5. Superposition of temperature factor plots of the two molecules of renin in the asymmetric unit of the cubic crystal form in the complex with inhibitor 10 (resolution 2.2 Å). The blue and the red curves correspond to the closed and open forms, respectively. The gap in the region 160 corresponds to a loop which is known to be undefined in all structures of renin described up to now.
Figure 7.
Figure 7. Hydrogen-bonding networks of renin bound to inhibitors (a) CGP 38′560 (1) and (b) 3.
  The above figures are reprinted by permission from Cell Press: Chem Biol (2000, 7, 493-504) copyright 2000.  
  Figures were selected by an automated process.  

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.
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21497958 S.Thangapandian, S.John, S.Sakkiah, and K.W.Lee (2011).
Potential virtual lead identification in the discovery of renin inhibitors: application of ligand and structure-based pharmacophore modeling approaches.
  Eur J Med Chem, 46, 2469-2476.  
20440278 A.E.Declèves, and K.Sharma (2010).
New pharmacological treatments for improving renal outcomes in diabetes.
  Nat Rev Nephrol, 6, 371-380.  
20730071 F.Cagnoni, C.A.Njwe, A.Zaninelli, A.R.Ricci, D.Daffra, A.D'Ospina, P.Preti, and M.Destro (2010).
Blocking the RAAS at different levels: an update on the use of the direct renin inhibitors alone and in combination.
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19433972 J.Bergset, E.Storozynsky, and J.D.Bisognano (2010).
Renin inhibition for hypertension: selecting the right role for a new class of drug.
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20664543 K.B.Biswas, A.H.Nabi, Y.Arai, T.Nakagawa, A.Ebihara, A.Ichihara, T.Watanabe, T.Inagami, and F.Suzuki (2010).
Aliskiren binds to renin and prorenin bound to (pro)renin receptor in vitro.
  Hypertens Res, 33, 1053-1059.  
20410659 M.Tanaka, M.Akahori, and H.Goto (2010).
[The pharmacological profile and clinical findings on aliskiren (Rasilez tablet), direct renin inhibitor].
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19367328 K.J.Wiggins, and D.J.Kelly (2009).
Aliskiren: a novel renoprotective agent or simply an alternative to ACE inhibitors?
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19176554 R.Brenke, D.Kozakov, G.Y.Chuang, D.Beglov, D.Hall, M.R.Landon, C.Mattos, and S.Vajda (2009).
Fragment-based identification of druggable 'hot spots' of proteins using Fourier domain correlation techniques.
  Bioinformatics, 25, 621-627.  
19855826 W.C.Van Voorhis, W.G.Hol, P.J.Myler, and L.J.Stewart (2009).
The role of medical structural genomics in discovering new drugs for infectious diseases.
  PLoS Comput Biol, 5, e1000530.
PDB codes: 3eiy 3ej0
18237679 A.H.Gradman, and R.Kad (2008).
Renin inhibition in hypertension.
  J Am Coll Cardiol, 51, 519-528.  
18765089 A.Stanton (2008).
Now that we have a direct Renin inhibitor, what should we do with it?
  Curr Hypertens Rep, 10, 194-200.  
18460596 A.Whaley-Connell, J.Habibi, S.A.Cooper, V.G.Demarco, M.R.Hayden, C.S.Stump, D.Link, C.M.Ferrario, and J.R.Sowers (2008).
Effect of renin inhibition and AT1R blockade on myocardial remodeling in the transgenic Ren2 rat.
  Am J Physiol Endocrinol Metab, 295, E103-E109.  
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.  
18437334 D.Westermann, R.Schmieder, H.P.Schultheiss, and C.Tschöpe (2008).
Renin inhibitors, clinical experience.
  J Mol Med, 86, 691-695.  
18307734 G.Wuerzner, and M.Azizi (2008).
Renin inhibition with aliskiren.
  Clin Exp Pharmacol Physiol, 35, 426-430.  
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.  
18345958 K.K.Sureshkumar, S.Vasudevan, R.J.Marcus, S.M.Hussain, and R.L.McGill (2008).
Aliskiren: clinical experience and future perspectives of renin inhibition.
  Expert Opin Pharmacother, 9, 825-837.  
18368379 M.Azizi (2008).
Direct renin inhibition: clinical pharmacology.
  J Mol Med, 86, 647-654.  
20409906 M.R.Hayden, and J.R.Sowers (2008).
Treating hypertension while protecting the vulnerable islet in the cardiometabolic syndrome.
  J Am Soc Hypertens, 2, 239-266.  
  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.  
18273042 V.L.Serebruany, A.Malinin, G.Barsness, J.Vahabi, and D.Atar (2008).
Effects of aliskiren, a renin inhibitor, on biomarkers of platelet activity, coagulation and fibrinolysis in subjects with multiple risk factors for vascular disease.
  J Hum Hypertens, 22, 303-310.  
18061877 E.F.Schmid, and D.A.Smith (2007).
Pharmaceutical R&D in the spotlight: why is there still unmet medical need?
  Drug Discov Today, 12, 998.  
17999663 N.C.Cohen (2007).
Structure-based drug design and the discovery of aliskiren (Tekturna): perseverance and creativity to overcome a R&D pipeline challenge.
  Chem Biol Drug Des, 70, 557-565.  
17700383 R.Sepehrdad, W.H.Frishman, C.T.Stier, and D.A.Sica (2007).
Direct inhibition of renin as a cardiovascular pharmacotherapy: focus on aliskiren.
  Cardiol Rev, 15, 242-256.  
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.  
17407105 V.Limongelli, L.Marinelli, S.Cosconati, H.A.Braun, B.Schmidt, and E.Novellino (2007).
Ensemble-Docking Approach on BACE-1: Pharmacophore Perception and Guidelines for Drug Design.
  ChemMedChem, 2, 667-678.  
16989601 E.O'Brien (2006).
Aliskiren: a renin inhibitor offering a new approach for the treatment of hypertension.
  Expert Opin Investig Drugs, 15, 1269-1277.  
16990928 J.P.Ebran, C.M.Jensen, S.A.Johannesen, J.Karaffa, K.B.Lindsay, R.Taaning, and T.Skrydstrup (2006).
Creating carbon-carbon bonds with samarium diiodide for the synthesis of modified amino acids and peptides.
  Org Biomol Chem, 4, 3553-3564.  
16960370 L.Yuan, J.Wu, R.E.Aluko, and X.Ye (2006).
Kinetics of renin inhibition by sodium houttuyfonate analogs.
  Biosci Biotechnol Biochem, 70, 2275-2280.  
16508564 M.Azizi, R.Webb, J.Nussberger, and N.K.Hollenberg (2006).
Renin inhibition with aliskiren: where are we now, and where are we going?
  J Hypertens, 24, 243-256.  
16914963 M.Azizi (2006).
Renin inhibition.
  Curr Opin Nephrol Hypertens, 15, 505-510.  
17073832 S.Vaidyanathan, J.Valencia, C.Kemp, C.Zhao, C.M.Yeh, M.N.Bizot, J.Denouel, H.A.Dieterich, and W.P.Dole (2006).
Lack of pharmacokinetic interactions of aliskiren, a novel direct renin inhibitor for the treatment of hypertension, with the antihypertensives amlodipine, valsartan, hydrochlorothiazide (HCTZ) and ramipril in healthy volunteers.
  Int J Clin Pract, 60, 1343-1356.  
17378372 T.Kushiro, H.Itakura, Y.Abo, H.Gotou, S.Terao, and D.L.Keefe (2006).
Aliskiren, a novel oral renin inhibitor, provides dose-dependent efficacy and placebo-like tolerability in Japanese patients with hypertension.
  Hypertens Res, 29, 997.  
19789728 Y.Suzaki, M.C.Prieto-Carrasquero, and H.Kobori (2006).
Intratubular Renin-Angiotensin System in Hypertension.
  Curr Hypertens Rev, 2, 151-157.  
16216580 A.A.Gorfe, and A.Caflisch (2005).
Functional plasticity in the substrate binding site of beta-secretase.
  Structure, 13, 1487-1498.  
15662231 J.M.Wood, C.R.Schnell, F.Cumin, J.Menard, and R.L.Webb (2005).
Aliskiren, a novel, orally effective renin inhibitor, lowers blood pressure in marmosets and spontaneously hypertensive rats.
  J Hypertens, 23, 417-426.  
16204988 R.Paruszewski, P.Jaworski, M.Bodnar, J.Dudkiewicz-Wilczyńska, 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.  
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.  
12110227 E.D.Zanders, D.S.Bailey, and P.M.Dean (2002).
Probes for chemical genomics by design.
  Drug Discov Today, 7, 711-718.  
12413557 P.Kuhn, K.Wilson, M.G.Patch, and R.C.Stevens (2002).
The genesis of high-throughput structure-based drug discovery using protein crystallography.
  Curr Opin Chem Biol, 6, 704-710.  
12045347 R.Paruszewski, P.Jaworski, I.Winiecka, J.Tautt, and J.Dudkiewicz (2002).
New renin inhibitors with pseudodipeptidic units in P(1)-P(1') and P(2')-P(3') positions.
  Chem Pharm Bull (Tokyo), 50, 850-853.  
11165173 D.Barrett, and S.Langston (2001).
Monitor: molecules and profiles.
  Drug Discov Today, 6, 52-53.  
11772235 G.J.Mizejewski (2001).
Peptides as receptor ligand drugs and their relationship to G-coupled signal transduction.
  Expert Opin Investig Drugs, 10, 1063-1073.  
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.  
11227042 N.D.Fisher, and N.K.Hollenberg (2001).
Is there a future for renin inhibitors?
  Expert Opin Investig Drugs, 10, 417-426.  
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.