7ZLL

Catalytic domain of UDP-Glucose Glycoprotein Glucosyltransferase from Chaetomium thermophilum in complex with the 5-[(morpholin-4-yl)methyl]quinolin-8-ol inhibitor

Summary for 7ZLL

• Entry DOI: 10.2210/pdb7zll/pdb
• Related: 6FSN 7ZHB 7ZKC 7ZLE
• Descriptor: UDP-glucose-glycoprotein glucosyltransferase-like protein, 5-(morpholin-4-ylmethyl)quinolin-8-ol, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: glycoprotein, misfolding, transferase, endoplasmic reticulum, gt24, 5-[(morpholin-4-yl)methyl]quinolin-8-ol
• Biological source: Chaetomium thermophilum
• Total number of polymer chains: 1
• Total formula weight: 36755.60

Authors

Roversi, P.,Zitzmann, N.,Bayo, Y.,Kantsadi, A.L.,Chandran, A.V. (deposition date: 2022-04-15, release date: 2023-04-26, Last modification date: 2024-11-06)

Primary citation

Guay, K.P.,Ibba, R.,Kiappes, J.L.,Vasiljevic, S.,Boni, F.,De Benedictis, M.,Zeni, I.,Le Cornu, J.D.,Hensen, M.,Chandran, A.V.,Kantsadi, A.L.,Caputo, A.T.,Blanco Capurro, J.I.,Bayo, Y.,Hill, J.C.,Hudson, K.,Lia, A.,Brun, J.,Withers, S.G.,Marti, M.,Biasini, E.,Santino, A.,De Rosa, M.,Milani, M.,Modenutti, C.P.,Hebert, D.N.,Zitzmann, N.,Roversi, P.
A quinolin-8-ol sub-millimolar inhibitor of UGGT, the ER glycoprotein folding quality control checkpoint.
Iscience, 26:107919-107919, 2023

PubMed Abstract: Misfolded glycoprotein recognition and endoplasmic reticulum (ER) retention are mediated by the ER glycoprotein folding quality control (ERQC) checkpoint enzyme, UDP-glucose glycoprotein glucosyltransferase (UGGT). UGGT modulation is a promising strategy for broad-spectrum antivirals, rescue-of-secretion therapy in rare disease caused by responsive mutations in glycoprotein genes, and many cancers, but to date no selective UGGT inhibitors are known. The small molecule 5-[(morpholin-4-yl)methyl]quinolin-8-ol (5M-8OH-Q) binds a UGGT "WY" conserved surface motif conserved across UGGTs but not present in other GT24 family glycosyltransferases. 5M-8OH-Q has a 47 μM binding affinity for UGGT as measured by ligand-enhanced fluorescence. , 5M-8OH-Q inhibits both human UGGT isoforms at concentrations higher than 750 μM. 5M-8OH-Q binding to UGGT appears to be mutually exclusive to M5-9 glycan binding in an competition experiment. A medicinal program based on 5M-8OH-Q will yield the next generation of UGGT inhibitors.

PubMed: 37822503
DOI: 10.1016/j.isci.2023.107919

Experimental method

X-RAY DIFFRACTION (1.649 Å)