2nn1
From Proteopedia
| Line 1: | Line 1: | ||
[[Image:2nn1.gif|left|200px]] | [[Image:2nn1.gif|left|200px]] | ||
| - | + | <!-- | |
| - | + | The line below this paragraph, containing "STRUCTURE_2nn1", creates the "Structure Box" on the page. | |
| - | + | You may change the PDB parameter (which sets the PDB file loaded into the applet) | |
| - | + | or the SCENE parameter (which sets the initial scene displayed when the page is loaded), | |
| - | + | or leave the SCENE parameter empty for the default display. | |
| - | + | --> | |
| - | + | {{STRUCTURE_2nn1| PDB=2nn1 | SCENE= }} | |
| - | + | ||
| - | + | ||
| - | }} | + | |
'''Structure of inhibitor binding to Carbonic Anhydrase I''' | '''Structure of inhibitor binding to Carbonic Anhydrase I''' | ||
| Line 28: | Line 25: | ||
[[Category: Christianson, D W.]] | [[Category: Christianson, D W.]] | ||
[[Category: Jude, K M.]] | [[Category: Jude, K M.]] | ||
| - | [[Category: | + | [[Category: Zinc metalloenzyme]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 09:39:15 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 06:39, 4 May 2008
Structure of inhibitor binding to Carbonic Anhydrase I
Overview
Despite the similarity in the active site pockets of carbonic anhydrase (CA) isozymes I and II, the binding affinities of benzenesulfonamide inhibitors are invariably higher with CA II as compared to CA I. To explore the structural basis of this molecular recognition phenomenon, we have designed and synthesized simple benzenesulfonamide inhibitors substituted at the para position with positively charged, negatively charged, and neutral functional groups, and we have determined the affinities and X-ray crystal structures of their enzyme complexes. The para-substituents are designed to bind in the midsection of the 15 A deep active site cleft, where interactions with enzyme residues and solvent molecules are possible. We find that a para-substituted positively charged amino group is more poorly tolerated in the active site of CA I compared with CA II. In contrast, a para-substituted negatively charged carboxylate substituent is tolerated equally well in the active sites of both CA isozymes. Notably, enzyme-inhibitor affinity increases upon neutralization of inhibitor charged groups by amidation or esterification. These results inform the design of short molecular linkers connecting the benzenesulfonamide group and a para-substituted tail group in "two-prong" CA inhibitors: an optimal linker segment will be electronically neutral, yet capable of engaging in at least some hydrogen bond interactions with protein residues and/or solvent. Microcalorimetric data reveal that inhibitor binding to CA I is enthalpically less favorable and entropically more favorable than inhibitor binding to CA II. This contrasting behavior may arise in part from differences in active site desolvation and the conformational entropy of inhibitor binding to each isozyme active site.
About this Structure
2NN1 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Structural analysis of charge discrimination in the binding of inhibitors to human carbonic anhydrases I and II., Srivastava DK, Jude KM, Banerjee AL, Haldar M, Manokaran S, Kooren J, Mallik S, Christianson DW, J Am Chem Soc. 2007 May 2;129(17):5528-37. Epub 2007 Apr 4. PMID:17407288 Page seeded by OCA on Sun May 4 09:39:15 2008
