1ww3

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[[Image:1ww3.gif|left|200px]]
[[Image:1ww3.gif|left|200px]]
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{{Structure
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|PDB= 1ww3 |SIZE=350|CAPTION= <scene name='initialview01'>1ww3</scene>, resolution 1.80&Aring;
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The line below this paragraph, containing "STRUCTURE_1ww3", creates the "Structure Box" on the page.
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|SITE=
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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|LIGAND= <scene name='pdbligand=NTF:N-TRIFLURO-ACETYL-BETA-D-GLUCOPYRANOSYLAMINE'>NTF</scene>, <scene name='pdbligand=PLP:PYRIDOXAL-5&#39;-PHOSPHATE'>PLP</scene>
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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|ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Phosphorylase Phosphorylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.1.1 2.4.1.1] </span>
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|GENE=
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|DOMAIN=
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{{STRUCTURE_1ww3| PDB=1ww3 | SCENE= }}
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|RELATEDENTRY=[[2prj|2PRJ]], [[1ww2|1WW2]]
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1ww3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ww3 OCA], [http://www.ebi.ac.uk/pdbsum/1ww3 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1ww3 RCSB]</span>
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'''Crystallographic studies on two bioisosteric analogues, N-acetyl-beta-D-glucopyranosylamine and N-trifluoroacetyl-beta-D-glucopyranosylamine, potent inhibitors of muscle glycogen phosphorylase'''
'''Crystallographic studies on two bioisosteric analogues, N-acetyl-beta-D-glucopyranosylamine and N-trifluoroacetyl-beta-D-glucopyranosylamine, potent inhibitors of muscle glycogen phosphorylase'''
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[[Category: Tiraidis, C.]]
[[Category: Tiraidis, C.]]
[[Category: Zographos, S E.]]
[[Category: Zographos, S E.]]
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[[Category: glycogenolysis]]
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[[Category: Glycogenolysis]]
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[[Category: type 2 diabetes]]
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[[Category: Type 2 diabetes]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 14:12:46 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 00:41:45 2008''
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Revision as of 11:12, 3 May 2008

Image:1ww3.gif

Template:STRUCTURE 1ww3

Crystallographic studies on two bioisosteric analogues, N-acetyl-beta-D-glucopyranosylamine and N-trifluoroacetyl-beta-D-glucopyranosylamine, potent inhibitors of muscle glycogen phosphorylase


Overview

Structure-based inhibitor design has led to the discovery of a number of potent inhibitors of glycogen phosphorylase b (GPb), N-acyl derivatives of beta-D-glucopyranosylamine, that bind at the catalytic site of the enzyme. The first good inhibitor in this class of compounds, N-acetyl-beta-D-glucopyranosylamine (NAG) (K(i) = 32 microM), has been previously characterized by biochemical, biological and crystallographic experiments at 2.3 angstroms resolution. Bioisosteric replacement of the acetyl group by trifluoroacetyl group resulted in an inhibitor, N-trifluoroacetyl-beta-D-glucopyranosylamine (NFAG), with a K(i) = 75 microM. To elucidate the structural basis of its reduced potency, we determined the ligand structure in complex with GPb at 1.8 angstroms resolution. To compare the binding mode of N-trifluoroacetyl derivative with that of the lead molecule, we also determined the structure of GPb-NAG complex at a higher resolution (1.9 angstroms). NFAG can be accommodated in the catalytic site of T-state GPb at approximately the same position as that of NAG and stabilize the T-state conformation of the 280 s loop by making several favourable contacts to Asn284 of this loop. The difference observed in the K(i) values of the two analogues can be interpreted in terms of subtle conformational changes of protein residues and shifts of water molecules in the vicinity of the catalytic site, variations in van der Waals interaction, and desolvation effects.

About this Structure

1WW3 is a Single protein structure of sequence from Oryctolagus cuniculus. Full crystallographic information is available from OCA.

Reference

Crystallographic studies on two bioisosteric analogues, N-acetyl-beta-D-glucopyranosylamine and N-trifluoroacetyl-beta-D-glucopyranosylamine, potent inhibitors of muscle glycogen phosphorylase., Anagnostou E, Kosmopoulou MN, Chrysina ED, Leonidas DD, Hadjiloi T, Tiraidis C, Zographos SE, Gyorgydeak Z, Somsak L, Docsa T, Gergely P, Kolisis FN, Oikonomakos NG, Bioorg Med Chem. 2006 Jan 1;14(1):181-9. Epub 2005 Oct 4. PMID:16213146 Page seeded by OCA on Sat May 3 14:12:46 2008

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