9FTQ
Drosophila golgi alpha-mannosidase II (dGMII) in complex with swainsonine-configured alkyl indolizidine
This is a non-PDB format compatible entry.
Summary for 9FTQ
| Entry DOI | 10.2210/pdb9ftq/pdb |
| Descriptor | Alpha-mannosidase 2, DI(HYDROXYETHYL)ETHER, swainsonine-configured alkyl indolizidine, ... (5 entities in total) |
| Functional Keywords | inhibitor, glycosyl hydrolase, hydrolase |
| Biological source | Drosophila melanogaster (fruit fly) |
| Total number of polymer chains | 1 |
| Total formula weight | 118757.04 |
| Authors | Bennett, M.,Koemans, T.,Overkleeft, H.S.,Davies, G.J. (deposition date: 2024-06-25, release date: 2024-10-09, Last modification date: 2024-10-23) |
| Primary citation | Koemans, T.,Bennett, M.,Ferraz, M.J.,Armstrong, Z.,Artola, M.,Aerts, J.M.F.G.,Codee, J.D.C.,Overkleeft, H.S.,Davies, G.J. Structure-guided design of C3-branched swainsonine as potent and selective human Golgi alpha-mannosidase (GMII) inhibitor. Chem.Commun.(Camb.), 60:11734-11737, 2024 Cited by PubMed Abstract: The human Golgi α-mannosidase, hGMII, removes two mannose residues from GlcNAc-ManGlcNAc to produce GlcNAcManGlcNAc, the precursor of all complex -glycans including tumour-associated ones. The natural product GMII inhibitor, swainsonine, blocks processing of cancer-associated -glycans, but also inhibits the four other human α-mannosidases, rendering it unsuitable for clinical use. Our previous structure-guided screening of iminosugar pyrrolidine and piperidine fragments identified two micromolar hGMII inhibitors occupying the enzyme active pockets in adjacent, partially overlapping sites. Here we demonstrate that fusing these fragments yields swainsonine-configured indolizidines featuring a C3-substituent that act as selective hGMII inhibitors. Our structure-guided GMII-selective inhibitor design complements a recent combinatorial approach that yielded similarly configured and substituted indolizidine GMII inhibitors, and holds promise for the potential future development of anti-cancer agents targeting Golgi -glycan processing. PubMed: 39318342DOI: 10.1039/d4cc04514a PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.47 Å) |
Structure validation
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