2iko

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
Line 1: Line 1:
-
[[Image:2iko.gif|left|200px]]
+
{{Seed}}
 +
[[Image:2iko.png|left|200px]]
<!--
<!--
Line 9: Line 10:
{{STRUCTURE_2iko| PDB=2iko | SCENE= }}
{{STRUCTURE_2iko| PDB=2iko | SCENE= }}
-
'''Crystal Structure of Human Renin Complexed with Inhibitor'''
+
===Crystal Structure of Human Renin Complexed with Inhibitor===
-
==Overview==
+
<!--
-
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.
+
The line below this paragraph, {{ABSTRACT_PUBMED_17113558}}, adds the Publication Abstract to the page
 +
(as it appears on PubMed at http://www.pubmed.gov), where 17113558 is the PubMed ID number.
 +
-->
 +
{{ABSTRACT_PUBMED_17113558}}
==Disease==
==Disease==
Line 30: Line 34:
[[Category: Inhibitor]]
[[Category: Inhibitor]]
[[Category: Renin]]
[[Category: Renin]]
-
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 07:36:44 2008''
+
 
 +
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 21:42:48 2008''

Revision as of 18:42, 28 July 2008

Image:2iko.png


PDB ID 2iko

Drag the structure with the mouse to rotate
2iko, resolution 1.90Å ()
Ligands:
Gene: REN (Homo sapiens)
Activity: Renin, with EC number 3.4.23.15
Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml



Contents

Crystal Structure of Human Renin Complexed with Inhibitor

Template:ABSTRACT PUBMED 17113558

Disease

Known disease associated with this structure: Renal tubular dysgenesis OMIM:[179820], Hyperproreninemia OMIM:[179820]

About this Structure

2IKO is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

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:17113558

Page seeded by OCA on Mon Jul 28 21:42:48 2008

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2iko"
Personal tools