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2hd6

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[[Image:2hd6.gif|left|200px]]
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{{STRUCTURE_2hd6| PDB=2hd6 | SCENE= }}
{{STRUCTURE_2hd6| PDB=2hd6 | SCENE= }}
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'''Crystal structure of the human carbonic anhydrase II in complex with a hypoxia-activatable sulfonamide.'''
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===Crystal structure of the human carbonic anhydrase II in complex with a hypoxia-activatable sulfonamide.===
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==Overview==
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An approach for designing bioreductive, hypoxia-activatable carbonic anhydrase (CA, EC 4.2.1.1) inhibitors targeting the tumor-associated isoforms is reported. Sulfonamides incorporating 3,3'-dithiodipropionamide/2,2'-dithiodibenzamido moieties were prepared and reduced enzymatically/chemically in conditions present in hypoxic tumors, leading to thiols. The X-ray crystal structure of the most promising compound, 4-(2-mercaptophenylcarboxamido)benzenesulfonamide, which as disulfide showed a K(I) against hCA IX of 653 nM (in reduced form of 9.1 nM), in adduct with hCA II showed the inhibitor making favorable interactions with Gln92, Val121, Phe131, Leu198, Thr199, Thr200, Pro201, and Pro202, whereas the sulfamoyl moiety was coordinated to the Zn2+ ion. The same interactions were preserved in the adduct with hCA IX, but in addition, a hydrogen bond between the SH moiety of the inhibitor and the amide nitrogen of Gln67 was evidenced, which may explain the almost 2 times more effective inhibition of the tumor-associated isozyme over the cytosolic isoform.
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(as it appears on PubMed at http://www.pubmed.gov), where 16942027 is the PubMed ID number.
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{{ABSTRACT_PUBMED_16942027}}
==About this Structure==
==About this Structure==
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==Reference==
==Reference==
Carbonic anhydrase inhibitors: Hypoxia-activatable sulfonamides incorporating disulfide bonds that target the tumor-associated isoform IX., De Simone G, Vitale RM, Di Fiore A, Pedone C, Scozzafava A, Montero JL, Winum JY, Supuran CT, J Med Chem. 2006 Sep 7;49(18):5544-51. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16942027 16942027]
Carbonic anhydrase inhibitors: Hypoxia-activatable sulfonamides incorporating disulfide bonds that target the tumor-associated isoform IX., De Simone G, Vitale RM, Di Fiore A, Pedone C, Scozzafava A, Montero JL, Winum JY, Supuran CT, J Med Chem. 2006 Sep 7;49(18):5544-51. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16942027 16942027]
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Refined structure of human carbonic anhydrase II at 2.0 A resolution., Eriksson AE, Jones TA, Liljas A, Proteins. 1988;4(4):274-82. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/3151019 3151019]
[[Category: Carbonate dehydratase]]
[[Category: Carbonate dehydratase]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Vitale, R M.]]
[[Category: Vitale, R M.]]
[[Category: Protein-inhibitor complex]]
[[Category: Protein-inhibitor complex]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 06:08:30 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 19:11:18 2008''

Revision as of 16:11, 28 July 2008

Image:2hd6.png

Template:STRUCTURE 2hd6

Crystal structure of the human carbonic anhydrase II in complex with a hypoxia-activatable sulfonamide.

Template:ABSTRACT PUBMED 16942027

About this Structure

2HD6 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Carbonic anhydrase inhibitors: Hypoxia-activatable sulfonamides incorporating disulfide bonds that target the tumor-associated isoform IX., De Simone G, Vitale RM, Di Fiore A, Pedone C, Scozzafava A, Montero JL, Winum JY, Supuran CT, J Med Chem. 2006 Sep 7;49(18):5544-51. PMID:16942027

Refined structure of human carbonic anhydrase II at 2.0 A resolution., Eriksson AE, Jones TA, Liljas A, Proteins. 1988;4(4):274-82. PMID:3151019

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