Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Structural and mechanistic insights into a lysosomal membrane enzyme HGSNAT involved in Sanfilippo syndrome.
Journal, issue, pages	Nat Commun, Vol. 15, Issue 1, Page 5388, Year 2024
Publish date	Jun 25, 2024
Authors	Boyang Zhao / Zhongzheng Cao / Yi Zheng / Phuong Nguyen / Alisa Bowen / Robert H Edwards / Robert M Stroud / Yi Zhou / Menno Van Lookeren Campagne / Fei Li /
PubMed Abstract	Heparan sulfate (HS) is degraded in lysosome by a series of glycosidases. Before the glycosidases can act, the terminal glucosamine of HS must be acetylated by the integral lysosomal membrane enzyme ...Heparan sulfate (HS) is degraded in lysosome by a series of glycosidases. Before the glycosidases can act, the terminal glucosamine of HS must be acetylated by the integral lysosomal membrane enzyme heparan-α-glucosaminide N-acetyltransferase (HGSNAT). Mutations of HGSNAT cause HS accumulation and consequently mucopolysaccharidosis IIIC, a devastating lysosomal storage disease characterized by progressive neurological deterioration and early death where no treatment is available. HGSNAT catalyzes a unique transmembrane acetylation reaction where the acetyl group of cytosolic acetyl-CoA is transported across the lysosomal membrane and attached to HS in one reaction. However, the reaction mechanism remains elusive. Here we report six cryo-EM structures of HGSNAT along the reaction pathway. These structures reveal a dimer arrangement and a unique structural fold, which enables the elucidation of the reaction mechanism. We find that a central pore within each monomer traverses the membrane and controls access of cytosolic acetyl-CoA to the active site at its luminal mouth where glucosamine binds. A histidine-aspartic acid catalytic dyad catalyzes the transfer reaction via a ternary complex mechanism. Furthermore, the structures allow the mapping of disease-causing variants and reveal their potential impact on the function, thus creating a framework to guide structure-based drug discovery efforts.
External links	Nat Commun / PubMed:38918376 / PubMed Central
Methods	EM (single particle)
Resolution	2.92 - 3.61 Å
Structure data	43319 8vkj EMDB-43319, PDB-8vkj: Cryo-EM structure of human HGSNAT bound with Acetyl-CoA Method: EM (single particle) / Resolution: 2.92 Å 43338 8vlg EMDB-43338, PDB-8vlg: Cryo-EM structure of human HGSNAT bound with Acetyl-CoA and substrate analog Method: EM (single particle) / Resolution: 3.15 Å 43339 8vli EMDB-43339, PDB-8vli: Cryo-EM structure of human HGSNAT bound with CoA and product analog Method: EM (single particle) / Resolution: 3.2 Å 43344 8vlu EMDB-43344, PDB-8vlu: Cryo-EM structure of human HGSNAT bound with CoA Method: EM (single particle) / Resolution: 3.12 Å 43345 8vlv EMDB-43345, PDB-8vlv: Cryo-EM structure of human HGSNAT in inactive state Method: EM (single particle) / Resolution: 3.49 Å 43348 8vly EMDB-43348, PDB-8vly: Cryo-EM structure of human HGSNAT in transition state Method: EM (single particle) / Resolution: 3.61 Å
Chemicals	ChemComp-NAG: 2-acetamido-2-deoxy-beta-D-glucopyranose ChemComp-ACO: ACETYL COENZYME A PDB-1acy: CRYSTAL STRUCTURE OF THE PRINCIPAL NEUTRALIZING SITE OF HIV-1 ChemComp-COA: COENZYME A PDB-1ac0*: GLUCOAMYLASE, GRANULAR STARCH-BINDING DOMAIN COMPLEX WITH CYCLODEXTRIN, NMR, MINIMIZED AVERAGE STRUCTURE
Source	homo sapiens (human)
Keywords	MEMBRANE PROTEIN / Lysosome / Transmembrane acetyltransferase / Acetyl-CoA / Heperan sulfate / TRANSFERASE/SUBSTRATE / substrate / Transferase-substrate analog complex / TRANSFERASE-SUBSTRATE complex / TRANSFERASE/INHIBITOR / CoA / product / TRANSFERASE-INHIBITOR complex / TRANSFERASE