6s4h: Difference between revisions
New page: '''Unreleased structure''' The entry 6s4h is ON HOLD Authors: Kyriakis, E., Solovou, T.G.A., Papaioannou, O.S.E., Skamnaki, V.T., Leonidas, D.D. Description: The crystal structure of g... |
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The | ==The crystal structure of glycogen phosphorylase in complex with 8== | ||
<StructureSection load='6s4h' size='340' side='right'caption='[[6s4h]], [[Resolution|resolution]] 2.45Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6s4h]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Oryctolagus_cuniculus Oryctolagus cuniculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6S4H OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6S4H FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=KUQ:(2~{R},3~{S},4~{R},5~{R},6~{S})-2-(hydroxymethyl)-6-(2-phenyl-1~{H}-imidazol-4-yl)oxane-3,4,5-triol'>KUQ</scene>, <scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</scene></td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><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></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6s4h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6s4h OCA], [http://pdbe.org/6s4h PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6s4h RCSB], [http://www.ebi.ac.uk/pdbsum/6s4h PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6s4h ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/PYGM_RABIT PYGM_RABIT]] Phosphorylase is an important allosteric enzyme in carbohydrate metabolism. Enzymes from different sources differ in their regulatory mechanisms and in their natural substrates. However, all known phosphorylases share catalytic and structural properties. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
C-Glucopyranosyl imidazoles, thiazoles, and an N-glucopyranosyl tetrazole were assessed in vitro and ex vivo for their inhibitory efficiency against isoforms of glycogen phosphorylase (GP; a validated pharmacological target for the development of anti-hyperglycaemic agents). Imidazoles proved to be more potent inhibitors than the corresponding thiazoles or the tetrazole. The most potent derivative has a 2-naphthyl substituent, a Ki value of 3.2 microM for hepatic glycogen phosphorylase, displaying also 60% inhibition of GP activity in HepG2 cells, compared to control vehicle treated cells, at 100 muM. X-Ray crystallography studies of the protein - inhibitor complexes revealed the importance of the architecture of inhibitor associated hydrogen bonds or sulfur sigma-hole bond interactions to Asn284 OD1, offering new insights to structure-based design efforts. Moreover, while the 2-glucopyranosyl-tetrazole seems to bind differently from the corresponding 1,2,3-triazole compound, the two inhibitors are equipotent. | |||
The architecture of hydrogen and sulfur sigma-hole interactions explain differences in the inhibitory potency of C-beta-d-glucopyranosyl thiazoles, imidazoles and an N-beta-d glucopyranosyl tetrazole for human liver glycogen phosphorylase and offer new insights to structure-based design.,Kyriakis E, Karra AG, Papaioannou O, Solovou T, Skamnaki VT, Liggri PGV, Zographos SE, Szennyes E, Bokor E, Kun S, Psarra AG, Somsak L, Leonidas DD Bioorg Med Chem. 2020 Jan 1;28(1):115196. doi: 10.1016/j.bmc.2019.115196. Epub, 2019 Nov 14. PMID:31767404<ref>PMID:31767404</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6s4h" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Oryctolagus cuniculus]] | |||
[[Category: Phosphorylase]] | |||
[[Category: Kyriakis, E]] | [[Category: Kyriakis, E]] | ||
[[Category: Skamnaki, V | [[Category: Leonidas, D D]] | ||
[[Category: Solovou, T | [[Category: Papaioannou, O S.E]] | ||
[[Category: | [[Category: Skamnaki, V T]] | ||
[[Category: | [[Category: Solovou, T G.A]] | ||
[[Category: C-beta-d-glucopyranosyl imidazole]] | |||
[[Category: Inhibitor]] | |||
[[Category: Transferase]] | |||
Latest revision as of 09:32, 19 February 2020
The crystal structure of glycogen phosphorylase in complex with 8The crystal structure of glycogen phosphorylase in complex with 8
Structural highlights
Function[PYGM_RABIT] Phosphorylase is an important allosteric enzyme in carbohydrate metabolism. Enzymes from different sources differ in their regulatory mechanisms and in their natural substrates. However, all known phosphorylases share catalytic and structural properties. Publication Abstract from PubMedC-Glucopyranosyl imidazoles, thiazoles, and an N-glucopyranosyl tetrazole were assessed in vitro and ex vivo for their inhibitory efficiency against isoforms of glycogen phosphorylase (GP; a validated pharmacological target for the development of anti-hyperglycaemic agents). Imidazoles proved to be more potent inhibitors than the corresponding thiazoles or the tetrazole. The most potent derivative has a 2-naphthyl substituent, a Ki value of 3.2 microM for hepatic glycogen phosphorylase, displaying also 60% inhibition of GP activity in HepG2 cells, compared to control vehicle treated cells, at 100 muM. X-Ray crystallography studies of the protein - inhibitor complexes revealed the importance of the architecture of inhibitor associated hydrogen bonds or sulfur sigma-hole bond interactions to Asn284 OD1, offering new insights to structure-based design efforts. Moreover, while the 2-glucopyranosyl-tetrazole seems to bind differently from the corresponding 1,2,3-triazole compound, the two inhibitors are equipotent. The architecture of hydrogen and sulfur sigma-hole interactions explain differences in the inhibitory potency of C-beta-d-glucopyranosyl thiazoles, imidazoles and an N-beta-d glucopyranosyl tetrazole for human liver glycogen phosphorylase and offer new insights to structure-based design.,Kyriakis E, Karra AG, Papaioannou O, Solovou T, Skamnaki VT, Liggri PGV, Zographos SE, Szennyes E, Bokor E, Kun S, Psarra AG, Somsak L, Leonidas DD Bioorg Med Chem. 2020 Jan 1;28(1):115196. doi: 10.1016/j.bmc.2019.115196. Epub, 2019 Nov 14. PMID:31767404[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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