2iku: Difference between revisions
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[[Image:2iku.gif|left|200px]] | [[Image:2iku.gif|left|200px]] | ||
'''Crystal Structure of Human Renin Complexed with Inhibitors''' | {{Structure | ||
|PDB= 2iku |SIZE=350|CAPTION= <scene name='initialview01'>2iku</scene>, resolution 2.600Å | |||
|SITE= | |||
|LIGAND= <scene name='pdbligand=LIY:6-ETHYL-5-[(2S)-1-(3-METHOXYPROPYL)-2-PHENYL-1,2,3,4-TETRAHYDROQUINOLIN-7-YL]PYRIMIDINE-2,4-DIAMINE'>LIY</scene> | |||
|ACTIVITY= [http://en.wikipedia.org/wiki/Renin Renin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.15 3.4.23.15] | |||
|GENE= | |||
}} | |||
'''Crystal Structure of Human Renin Complexed with Inhibitors''' | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
2IKU is a [ | 2IKU is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2IKU OCA]. | ||
==Reference== | ==Reference== | ||
Binding thermodynamics of substituted diaminopyrimidine renin inhibitors., Sarver RW, Peevers J, Cody WL, Ciske FL, Dyer J, Emerson SD, Hagadorn JC, Holsworth DD, Jalaie M, Kaufman M, Mastronardi M, McConnell P, Powell NA, Quin J 3rd, Van Huis CA, Zhang E, Mochalkin I, Anal Biochem. 2007 Jan 1;360(1):30-40. Epub 2006 Oct 30. PMID:[http:// | Binding thermodynamics of substituted diaminopyrimidine renin inhibitors., Sarver RW, Peevers J, Cody WL, Ciske FL, Dyer J, Emerson SD, Hagadorn JC, Holsworth DD, Jalaie M, Kaufman M, Mastronardi M, McConnell P, Powell NA, Quin J 3rd, Van Huis CA, Zhang E, Mochalkin I, Anal Biochem. 2007 Jan 1;360(1):30-40. Epub 2006 Oct 30. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17113558 17113558] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Renin]] | [[Category: Renin]] | ||
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[[Category: LIY]] | [[Category: LIY]] | ||
[[Category: drug design]] | [[Category: drug design]] | ||
[[Category: | [[Category: inhibitor]] | ||
[[Category: renin]] | [[Category: renin]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 17:30:44 2008'' | ||
Revision as of 18:30, 20 March 2008
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| , resolution 2.600Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | |||||||
| Activity: | Renin, with EC number 3.4.23.15 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal Structure of Human Renin Complexed with Inhibitors
OverviewOverview
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.
DiseaseDisease
Known diseases associated with this structure: Hyperproreninemia OMIM:[179820], Renal tubular dysgenesis OMIM:[179820]
About this StructureAbout this Structure
2IKU is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Binding thermodynamics of substituted diaminopyrimidine renin inhibitors., Sarver RW, Peevers J, Cody WL, Ciske FL, Dyer J, Emerson SD, Hagadorn JC, Holsworth DD, Jalaie M, Kaufman M, Mastronardi M, McConnell P, Powell NA, Quin J 3rd, Van Huis CA, Zhang E, Mochalkin I, Anal Biochem. 2007 Jan 1;360(1):30-40. Epub 2006 Oct 30. PMID:17113558
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