2fnn
From Proteopedia
(New page: 200px<br /> <applet load="2fnn" size="450" color="white" frame="true" align="right" spinBox="true" caption="2fnn, resolution 1.8Å" /> '''Activation of human ...) |
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caption="2fnn, resolution 1.8Å" /> | caption="2fnn, resolution 1.8Å" /> | ||
'''Activation of human carbonic anhydrase II by exogenous proton donors'''<br /> | '''Activation of human carbonic anhydrase II by exogenous proton donors'''<br /> | ||
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==Overview== | ==Overview== | ||
Small molecule rescue of mutant forms of human carbonic anhydrase II (HCA, II) occurs by participation of exogenous donors/acceptors in the proton, transfer pathway between the zinc-bound water and solution. To examine, more thoroughly the energetics of this activation, we have constructed a, mutant, H64W HCA II, which we have shown is activated by 4-methylimidazole, (4-MI) by a mechanism involving the binding of 4-MI to the side chain of, Trp-64 approximately 8 A from the zinc. A series of experiments are, consistent with the activation of H64W HCA II by the interaction of, imidazole and pyridine derivatives as exogenous proton donors with the, indole ring of Trp-64; these experiments include pH profiles and H/D, solvent isotope effects consistent with proton transfer, observation of, approximately fourfold greater activation with the mutant containing, Trp-64 compared with Gly-64, and the observation by x-ray crystallography, of the binding of 4-MI associated with the indole side chain of Trp-64 in, W5A-H64W HCA II. Proton donors bound at the less flexible side chain of, Trp-64 in W5A-H64W HCA II do not show activation, but such donors bound at, the more flexible Trp-64 of H64W HCA II do show activation, supporting, suggestions that conformational mobility of the binding site is associated, with more efficient proton transfer. Evaluation using Marcus theory showed, that the activation of H64W HCA II by these proton donors was reflected in, the work functions w(r) and w(p) rather than in the intrinsic Marcus, barrier itself, consistent with the role of solvent reorganization in, catalysis. | Small molecule rescue of mutant forms of human carbonic anhydrase II (HCA, II) occurs by participation of exogenous donors/acceptors in the proton, transfer pathway between the zinc-bound water and solution. To examine, more thoroughly the energetics of this activation, we have constructed a, mutant, H64W HCA II, which we have shown is activated by 4-methylimidazole, (4-MI) by a mechanism involving the binding of 4-MI to the side chain of, Trp-64 approximately 8 A from the zinc. A series of experiments are, consistent with the activation of H64W HCA II by the interaction of, imidazole and pyridine derivatives as exogenous proton donors with the, indole ring of Trp-64; these experiments include pH profiles and H/D, solvent isotope effects consistent with proton transfer, observation of, approximately fourfold greater activation with the mutant containing, Trp-64 compared with Gly-64, and the observation by x-ray crystallography, of the binding of 4-MI associated with the indole side chain of Trp-64 in, W5A-H64W HCA II. Proton donors bound at the less flexible side chain of, Trp-64 in W5A-H64W HCA II do not show activation, but such donors bound at, the more flexible Trp-64 of H64W HCA II do show activation, supporting, suggestions that conformational mobility of the binding site is associated, with more efficient proton transfer. Evaluation using Marcus theory showed, that the activation of H64W HCA II by these proton donors was reflected in, the work functions w(r) and w(p) rather than in the intrinsic Marcus, barrier itself, consistent with the role of solvent reorganization in, catalysis. | ||
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| - | ==Disease== | ||
| - | Known disease associated with this structure: Osteopetrosis, autosomal recessive 3, with renal tubular acidosis OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=611492 611492]] | ||
==About this Structure== | ==About this Structure== | ||
| - | 2FNN is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with ZN and 4MZ as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Carbonate_dehydratase Carbonate dehydratase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.2.1.1 4.2.1.1] Full crystallographic information is available from [http:// | + | 2FNN is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=ZN:'>ZN</scene> and <scene name='pdbligand=4MZ:'>4MZ</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Carbonate_dehydratase Carbonate dehydratase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.2.1.1 4.2.1.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2FNN OCA]. |
==Reference== | ==Reference== | ||
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[[Category: proton transfer]] | [[Category: proton transfer]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 15:23:52 2008'' |
Revision as of 13:23, 23 January 2008
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Activation of human carbonic anhydrase II by exogenous proton donors
Overview
Small molecule rescue of mutant forms of human carbonic anhydrase II (HCA, II) occurs by participation of exogenous donors/acceptors in the proton, transfer pathway between the zinc-bound water and solution. To examine, more thoroughly the energetics of this activation, we have constructed a, mutant, H64W HCA II, which we have shown is activated by 4-methylimidazole, (4-MI) by a mechanism involving the binding of 4-MI to the side chain of, Trp-64 approximately 8 A from the zinc. A series of experiments are, consistent with the activation of H64W HCA II by the interaction of, imidazole and pyridine derivatives as exogenous proton donors with the, indole ring of Trp-64; these experiments include pH profiles and H/D, solvent isotope effects consistent with proton transfer, observation of, approximately fourfold greater activation with the mutant containing, Trp-64 compared with Gly-64, and the observation by x-ray crystallography, of the binding of 4-MI associated with the indole side chain of Trp-64 in, W5A-H64W HCA II. Proton donors bound at the less flexible side chain of, Trp-64 in W5A-H64W HCA II do not show activation, but such donors bound at, the more flexible Trp-64 of H64W HCA II do show activation, supporting, suggestions that conformational mobility of the binding site is associated, with more efficient proton transfer. Evaluation using Marcus theory showed, that the activation of H64W HCA II by these proton donors was reflected in, the work functions w(r) and w(p) rather than in the intrinsic Marcus, barrier itself, consistent with the role of solvent reorganization in, catalysis.
About this Structure
2FNN is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Carbonate dehydratase, with EC number 4.2.1.1 Full crystallographic information is available from OCA.
Reference
Location of binding sites in small molecule rescue of human carbonic anhydrase II., Bhatt D, Fisher SZ, Tu C, McKenna R, Silverman DN, Biophys J. 2007 Jan 15;92(2):562-70. Epub 2006 Oct 27. PMID:17071654
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