8EGV

Co-crystal structure of Chaetomium glucosidase with compound 12

PDB DOI: https://doi.org/10.2210/pdb8EGV/pdb

Classification: HYDROLASE/INHIBITOR
Organism(s): Thermochaetoides thermophila DSM 1495
Expression System: Homo sapiens
Mutation(s): No

Deposited: 2022-09-13 Released: 2023-02-22
Deposition Author(s): Karade, S.S., Mariuzza, R.A.
Funding Organization(s): Not funded

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.09 ?
R-Value Free: 0.227
R-Value Work: 0.186
R-Value Observed: 0.188

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.3 of the entry. See complete history.

Literature

Structure-Based Design of Potent Iminosugar Inhibitors of Endoplasmic Reticulum alpha-Glucosidase I with Anti-SARS-CoV-2 Activity.

Karade, S.S., Franco, E.J., Rojas, A.C., Hanrahan, K.C., Kolesnikov, A., Yu, W., MacKerell Jr., A.D., Hill, D.C., Weber, D.J., Brown, A.N., Treston, A.M., Mariuzza, R.A.

(2023) J Med Chem 66: 2744-2760

PubMed: 36762932 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/acs.jmedchem.2c01750
Primary Citation of Related Structures:
7R6J, 7RD2, 7REV, 8E3J, 8E3P, 8E4I, 8E4K, 8E4Z, 8E5U, 8E6G, 8ECW, 8EGV, 8EHP, 8EID, 8EKN, 8ELE, 8EPJ, 8EPO, 8EPR, 8EQ7, 8EQX, 8ER4, 8ETL, 8ETO, 8EUD, 8EUR, 8EUT, 8EUX

PubMed Abstract:
Enveloped viruses depend on the host endoplasmic reticulum (ER) quality control (QC) machinery for proper glycoprotein folding. The endoplasmic reticulum quality control (ERQC) enzyme α-glucosidase I (α-GluI) is an attractive target for developing broad-spectrum antivirals. We synthesized 28 inhibitors designed to interact with all four subsites of the α-GluI active site. These inhibitors are derivatives of the iminosugars 1-deoxynojirimycin (1-DNJ) and valiolamine. Crystal structures of ER α-GluI bound to 25 1-DNJ and three valiolamine derivatives revealed the basis for inhibitory potency. We established the structure-activity relationship (SAR) and used the Site Identification by Ligand Competitive Saturation (SILCS) method to develop a model for predicting α-GluI inhibition. We screened the compounds against SARS-CoV-2 in vitro to identify those with greater antiviral activity than the benchmark α-glucosidase inhibitor UV-4. These host-targeting compounds are candidates for investigation in animal models of SARS-CoV-2 and for testing against other viruses that rely on ERQC for correct glycoprotein folding.

Organizational Affiliation

University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, Maryland 20850, United States.

Macromolecule Content

Total Structure Weight: 189.47 kDa
Atom Count: 13,105
Modelled Residue Count: 1,529
Deposited Residue Count: 1,638
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Chaetomium alpha glucosidase	A, B	819	Thermochaetoides thermophila DSM 1495	Mutation(s): 0 Gene Names: CTHT_0061620 EC: 3.2.1.106
UniProt
Find proteins for G0SFD1 (Chaetomium thermophilum (strain DSM 1495 / CBS 144.50 / IMI 039719)) Explore G0SFD1 Go to UniProtKB: G0SFD1
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	G0SFD1
Glycosylation
Glycosylation Sites: 1	Glycosylation Focus chain B
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 5 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
WJF (Subject of Investigation/LOI) Query on WJF Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain N [auth B] MOL2 format, chain C [auth A] MOL2 format, chain N [auth B] mmCIF format, chain C [auth A] mmCIF format, chain N [auth B]	C [auth A], N [auth B]	(2R,3R,4R,5S)-1-{2-[4-(2-{[(5M)-3-chloro-5-(1,2,4-oxadiazol-3-yl)phenyl]amino}ethyl)phenyl]ethyl}-2-(hydroxymethyl)piperidine-3,4,5-triol C₂₄ H₂₉ Cl N₄ O₅ IECIOXOWPHIYDY-KAOXLYBCSA-N		Interactions Focus chain C [auth A] Focus chain N [auth B] Interactions & Density Focus chain C [auth A] Focus chain N [auth B]
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain O [auth B] MOL2 format, chain O [auth B] mmCIF format, chain O [auth B]	O [auth B]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-N		Interactions Focus chain O [auth B] Interactions & Density Focus chain O [auth B]
BTB Query on BTB Download Ideal Coordinates CCD File SDF format, chain P [auth B] MOL2 format, chain P [auth B] mmCIF format, chain P [auth B]	P [auth B]	2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL C₈ H₁₉ N O₅ OWMVSZAMULFTJU-UHFFFAOYSA-N		Interactions Focus chain P [auth B] Interactions & Density Focus chain P [auth B]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain K [auth A] SDF format, chain G [auth A] SDF format, chain H [auth A] SDF format, chain I [auth A] SDF format, chain J [auth A] SDF format, chain L [auth A] SDF format, chain M [auth A] SDF format, chain R [auth B] SDF format, chain S [auth B] SDF format, chain T [auth B] SDF format, chain U [auth B] MOL2 format, chain K [auth A] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] MOL2 format, chain I [auth A] MOL2 format, chain J [auth A] MOL2 format, chain L [auth A] MOL2 format, chain M [auth A] MOL2 format, chain R [auth B] MOL2 format, chain S [auth B] MOL2 format, chain T [auth B] MOL2 format, chain U [auth B] mmCIF format, chain K [auth A] mmCIF format, chain G [auth A] mmCIF format, chain H [auth A] mmCIF format, chain I [auth A] mmCIF format, chain J [auth A] mmCIF format, chain L [auth A] mmCIF format, chain M [auth A] mmCIF format, chain R [auth B] mmCIF format, chain S [auth B] mmCIF format, chain T [auth B] mmCIF format, chain U [auth B]	G [auth A] H [auth A] I [auth A] J [auth A] K [auth A] G [auth A], H [auth A], I [auth A], J [auth A], K [auth A], L [auth A], M [auth A], R [auth B], S [auth B], T [auth B], U [auth B]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain K [auth A] Focus chain L [auth A] Focus chain M [auth A] Focus chain R [auth B] Focus chain S [auth B] Focus chain T [auth B] Focus chain U [auth B] Interactions & Density Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain K [auth A] Focus chain L [auth A] Focus chain M [auth A] Focus chain R [auth B] Focus chain S [auth B] Focus chain T [auth B] Focus chain U [auth B]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain E [auth A] SDF format, chain F [auth A] SDF format, chain Q [auth B] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain Q [auth B] mmCIF format, chain D [auth A] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A] mmCIF format, chain Q [auth B]	D [auth A], E [auth A], F [auth A], Q [auth B]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain Q [auth B] Interactions & Density Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain Q [auth B]