View source for 8rvk


==Maltodextrin phosphorylase (MalP) in complex with a alpha-1,2-cyclophellitol analogue==
<StructureSection load='8rvk' size='340' side='right'caption='[[8rvk]], [[Resolution|resolution]] 2.18&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8rvk]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8RVK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8RVK FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.18&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1H3V:(3~{a}~{R},4~{R},5~{R},6~{R},7~{a}~{S})-6-(hydroxymethyl)-4,5-bis(oxidanyl)-3~{a},4,5,6,7,7~{a}-hexahydro-3~{H}-1,3-benzoxazol-2-one'>A1H3V</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=LLP:(2S)-2-AMINO-6-[[3-HYDROXY-2-METHYL-5-(PHOSPHONOOXYMETHYL)PYRIDIN-4-YL]METHYLIDENEAMINO]HEXANOIC+ACID'>LLP</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8rvk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8rvk OCA], [https://pdbe.org/8rvk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8rvk RCSB], [https://www.ebi.ac.uk/pdbsum/8rvk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8rvk ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Glycoside hydrolases (glycosidases) take part in myriad biological processes and are important therapeutic targets. Competitive and mechanism-based inhibitors are useful tools to dissect their biological role and comprise a good starting point for drug discovery. The natural product, cyclophellitol, a mechanism-based, covalent and irreversible retaining beta-glucosidase inhibitor has inspired the design of diverse alpha- and beta-glycosidase inhibitor and activity-based probe scaffolds. Here, we sought to deepen our understanding of the structural and functional requirements of cyclophellitol-type compounds for effective human alpha-glucosidase inhibition. We synthesized a comprehensive set of alpha-configured 1,2- and 1,5a-cyclophellitol analogues bearing a variety of electrophilic traps. The inhibitory potency of these compounds was assessed towards both lysosomal and ER retaining alpha-glucosidases. These studies revealed the 1,5a-cyclophellitols to be the most potent retaining alpha-glucosidase inhibitors, with the nature of the electrophile determining inhibitory mode of action (covalent or non-covalent). DFT calculations support the ability of the 1,5a-cyclophellitols, but not the 1,2-congeners, to adopt conformations that mimic either the Michaelis complex or transition state of alpha-glucosidases.

Conformational and Electronic Variations in 1,2- and 1,5a-Cyclophellitols and their Impact on Retaining alpha-Glucosidase Inhibition.,Ofman TP, Heming JJA, Nin-Hill A, Kullmer F, Moran E, Bennett M, Steneker R, Klein AM, Ruijgrok G, Kok K, Armstrong ZWB, Aerts JMFG, van der Marel GA, Rovira C, Davies GJ, Artola M, Codee JDC, Overkleeft HS Chemistry. 2024 Apr 16:e202400723. doi: 10.1002/chem.202400723. PMID:38623783<ref>PMID:38623783</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8rvk" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Escherichia coli K-12]]
[[Category: Large Structures]]
[[Category: Bennett M]]
[[Category: Davies GJ]]
[[Category: Ofman TP]]
[[Category: Overkleeft HS]]