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1b3o
From Proteopedia
(New page: 200px<br /> <applet load="1b3o" size="450" color="white" frame="true" align="right" spinBox="true" caption="1b3o, resolution 2.90Å" /> '''TERNARY COMPLEX OF ...) |
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| - | [[Image:1b3o.gif|left|200px]]<br /> | + | [[Image:1b3o.gif|left|200px]]<br /><applet load="1b3o" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1b3o" size=" | + | |
caption="1b3o, resolution 2.90Å" /> | caption="1b3o, resolution 2.90Å" /> | ||
'''TERNARY COMPLEX OF HUMAN TYPE-II INOSINE MONOPHOSPHATE DEHYDROGENASE WITH 6-CL-IMP AND SELENAZOLE ADENINE DINUCLEOTIDE'''<br /> | '''TERNARY COMPLEX OF HUMAN TYPE-II INOSINE MONOPHOSPHATE DEHYDROGENASE WITH 6-CL-IMP AND SELENAZOLE ADENINE DINUCLEOTIDE'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Inosine monophosphate dehydrogenase (IMPDH) controls a key metabolic step | + | Inosine monophosphate dehydrogenase (IMPDH) controls a key metabolic step in the regulation of cell growth and differentiation. This step is the NAD-dependent oxidation of inosine 5' monophosphate (IMP) to xanthosine 5' monophosphate, the rate-limiting step in the synthesis of the guanine nucleotides. Two isoforms of IMPDH have been identified, one of which (type II) is significantly up- regulated in neoplastic and differentiating cells. As such, it has been identified as a major target in antitumor and immunosuppressive drug design. We present here the 2.9-A structure of a ternary complex of the human type II isoform of IMPDH. The complex contains the substrate analogue 6-chloropurine riboside 5'-monophosphate (6-Cl-IMP) and the NAD analogue selenazole-4-carboxamide adenine dinucleotide, the selenium derivative of the active metabolite of the antitumor drug tiazofurin. The enzyme forms a homotetramer, with the dinucleotide binding at the monomer-monomer interface. The 6 chloro-substituted purine base is dehalogenated, forming a covalent adduct at C6 with Cys-331. The dinucleotide selenazole base is stacked against the 6-Cl-IMP purine ring in an orientation consistent with the B-side stereochemistry of hydride transfer seen with NAD. The adenosine end of the ligand interacts with residues not conserved between the type I and type II isoforms, suggesting strategies for the design of isoform-specific agents. |
==About this Structure== | ==About this Structure== | ||
| - | 1B3O 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 CPR, SAE and UNX as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/IMP_dehydrogenase IMP dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.205 1.1.1.205] Full crystallographic information is available from [http:// | + | 1B3O 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=CPR:'>CPR</scene>, <scene name='pdbligand=SAE:'>SAE</scene> and <scene name='pdbligand=UNX:'>UNX</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/IMP_dehydrogenase IMP dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.205 1.1.1.205] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1B3O OCA]. |
==Reference== | ==Reference== | ||
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[[Category: IMP dehydrogenase]] | [[Category: IMP dehydrogenase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Colby, T | + | [[Category: Colby, T D.]] |
| - | [[Category: Goldstein, B | + | [[Category: Goldstein, B M.]] |
| - | [[Category: Strickler, M | + | [[Category: Strickler, M D.]] |
[[Category: Vanderveen, K.]] | [[Category: Vanderveen, K.]] | ||
[[Category: CPR]] | [[Category: CPR]] | ||
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[[Category: impdh]] | [[Category: impdh]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 11:51:06 2008'' |
Revision as of 09:51, 21 February 2008
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TERNARY COMPLEX OF HUMAN TYPE-II INOSINE MONOPHOSPHATE DEHYDROGENASE WITH 6-CL-IMP AND SELENAZOLE ADENINE DINUCLEOTIDE
Overview
Inosine monophosphate dehydrogenase (IMPDH) controls a key metabolic step in the regulation of cell growth and differentiation. This step is the NAD-dependent oxidation of inosine 5' monophosphate (IMP) to xanthosine 5' monophosphate, the rate-limiting step in the synthesis of the guanine nucleotides. Two isoforms of IMPDH have been identified, one of which (type II) is significantly up- regulated in neoplastic and differentiating cells. As such, it has been identified as a major target in antitumor and immunosuppressive drug design. We present here the 2.9-A structure of a ternary complex of the human type II isoform of IMPDH. The complex contains the substrate analogue 6-chloropurine riboside 5'-monophosphate (6-Cl-IMP) and the NAD analogue selenazole-4-carboxamide adenine dinucleotide, the selenium derivative of the active metabolite of the antitumor drug tiazofurin. The enzyme forms a homotetramer, with the dinucleotide binding at the monomer-monomer interface. The 6 chloro-substituted purine base is dehalogenated, forming a covalent adduct at C6 with Cys-331. The dinucleotide selenazole base is stacked against the 6-Cl-IMP purine ring in an orientation consistent with the B-side stereochemistry of hydride transfer seen with NAD. The adenosine end of the ligand interacts with residues not conserved between the type I and type II isoforms, suggesting strategies for the design of isoform-specific agents.
About this Structure
1B3O is a Single protein structure of sequence from Homo sapiens with , and as ligands. Active as IMP dehydrogenase, with EC number 1.1.1.205 Full crystallographic information is available from OCA.
Reference
Crystal structure of human type II inosine monophosphate dehydrogenase: implications for ligand binding and drug design., Colby TD, Vanderveen K, Strickler MD, Markham GD, Goldstein BM, Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3531-6. PMID:10097070
Page seeded by OCA on Thu Feb 21 11:51:06 2008
