2HKA

Crystal structure of bovine NPC2 and cholesterol sulfate complex

Summary for 2HKA

• Entry DOI: 10.2210/pdb2hka/pdb
• Descriptor: Epididymal secretory protein E1, 2-acetamido-2-deoxy-beta-D-glucopyranose, ACETATE ION, ... (7 entities in total)
• Functional Keywords: beta barrel, lipid binding protein
• Biological source: Bos taurus (cattle)
• Cellular location: Secreted: P79345
• Total number of polymer chains: 3
• Total formula weight: 46321.93

Authors

Xu, S.,Gu, L.,Benoff, B.,Stock, A.M. (deposition date: 2006-07-03, release date: 2007-06-26, Last modification date: 2024-10-30)

Primary citation

Xu, S.,Benoff, B.,Liou, H.-L.,Lobel, P.,Stock, A.M.
Structural Basis of Sterol Binding by NPC2, a Lysosomal Protein Deficient in Niemann-Pick Type C2 Disease
J.Biol.Chem., 282:23525-23531, 2007

PubMed Abstract: NPC2 is a small lysosomal glycoprotein that binds cholesterol with submicromolar affinity. Deficiency in NPC2 is the cause of Niemann-Pick type C2 disease, a fatal neurovisceral disorder characterized by accumulation of cholesterol in lysosomes. Here we report the crystal structure of bovine NPC2 bound to cholesterol-3-O-sulfate, an analog that binds with greater apparent affinity than cholesterol. Structures of both apo-bound and sterol-bound NPC2 were observed within the same crystal lattice, with an asymmetric unit containing one molecule of apoNPC2 and two molecules of sterol-bound NPC2. As predicted from a previously determined structure of apoNPC2, the sterol binds in a deep hydrophobic pocket sandwiched between the two beta-sheets of NPC2, with only the sulfate substituent of the ligand exposed to solvent. In the two available structures of apoNPC2, the incipient ligand-binding pocket, which ranges from a loosely packed hydrophobic core to a small tunnel, is too small to accommodate cholesterol. In the presence of sterol, the pocket expands, facilitated by a slight separation of the beta-strands and substantial reorientation of some side chains, resulting in a perfect molding of the pocket around the hydrocarbon portion of cholesterol. A notable feature is the repositioning of two aromatic residues at the tunnel entrance that are essential for NPC2 function. The NPC2 structures provide evidence of a malleable binding site, consistent with the previously documented broad range of sterol ligand specificity.

PubMed: 17573352
DOI: 10.1074/jbc.M703848200

Experimental method

X-RAY DIFFRACTION (1.81 Å)