PDBsum entry 2iku

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Hydrolase PDB id
Protein chain
337 a.a. *
LIY ×2
Waters ×85
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Crystal structure of human renin complexed with inhibitors
Structure: Renin. Chain: a, b. Synonym: angiotensinogenase. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_cell: ovary
Biol. unit: Hexamer (from PDB file)
2.60Å     R-factor:   0.214     R-free:   0.256
Authors: I.Mochalkin
Key ref: R.W.Sarver et al. (2007). Binding thermodynamics of substituted diaminopyrimidine renin inhibitors. Anal Biochem, 360, 30-40. PubMed id: 17113558 DOI: 10.1016/j.ab.2006.10.017
02-Oct-06     Release date:   05-Dec-06    
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Protein chains
Pfam   ArchSchema ?
P00797  (RENI_HUMAN) -  Renin
406 a.a.
337 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/j.ab.2006.10.017 Anal Biochem 360:30-40 (2007)
PubMed id: 17113558  
Binding thermodynamics of substituted diaminopyrimidine renin inhibitors.
R.W.Sarver, J.Peevers, W.L.Cody, F.L.Ciske, J.Dyer, S.D.Emerson, J.C.Hagadorn, D.D.Holsworth, M.Jalaie, M.Kaufman, M.Mastronardi, P.McConnell, N.A.Powell, J.Quin, C.A.Van Huis, E.Zhang, I.Mochalkin.
Renin is an aspartyl protease involved in the production of angiotensin II, a potent vasoconstrictor. Renin inhibitors can prevent blood vessel constriction and therefore could be useful for the treatment of hypertension. High-throughput screening efforts identified a small molecule renin inhibitor with a core substituted diaminopyrimidine ring. Parallel medicinal chemistry efforts based on this lead resulted in compound 1. A complex of 1 bound to renin was crystallized, and structural data were obtained by X-ray diffraction. The structure indicated that there were adjacent unoccupied binding pockets. Synthetic efforts were initiated to extend functionality into these pockets so as to improve affinity and adjust pharmacokinetic parameters. Thermodynamics data for inhibitor binding to renin were also collected using isothermal titration calorimetry. These data were used to help guide inhibitor optimization by suggesting molecular alterations to improve binding affinity from both thermodynamic and structural perspectives. The addition of a methoxypropyl group extending into the S3 subpocket improved inhibitor affinity and resulted in greater binding enthalpy. Initial additions to the pyrimidine ring template that extended into the large hydrophobic S2 pocket did not improve affinity and dramatically altered the thermodynamic driving force for the binding interaction. Binding of the core template was enthalpically driven, whereas binding of initial inhibitors with S2 extensions was both enthalpically and entropically driven but lost significant binding enthalpy. Additional electrostatic interactions were then incorporated into the S2 extension to improve binding enthalpy while taking advantage of the favorable entropy.

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.  
21288305 A.Schön, N.Madani, A.B.Smith, J.M.Lalonde, and E.Freire (2011).
Some binding-related drug properties are dependent on thermodynamic signature.
  Chem Biol Drug Des, 77, 161-165.  
  20186976 N.Singh, and A.Warshel (2010).
Absolute binding free energy calculations: on the accuracy of computational scoring of protein-ligand interactions.
  Proteins, 78, 1705-1723.  
19793186 E.Freire (2009).
A thermodynamic approach to the affinity optimization of drug candidates.
  Chem Biol Drug Des, 74, 468-472.  
18765089 A.Stanton (2008).
Now that we have a direct Renin inhibitor, what should we do with it?
  Curr Hypertens Rep, 10, 194-200.  
18703160 E.Freire (2008).
Do enthalpy and entropy distinguish first in class from best in class?
  Drug Discov Today, 13, 869-874.  
18469827 K.Strebhardt, A.Ullrich, and P.Ehrlich (2008).
Paul Ehrlich's magic bullet concept: 100 years of progress.
  Nat Rev Cancer, 8, 473-480.  
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