3RIC: Crystal Structure of D48V||A47D mutant of Human Glycolipid Transfer Protein complexed with 3-O-sulfo-galactosylceramide containing nervonoyl acyl chain (24:1)

Citation:
Abstract
Human glycolipid transfer protein (GLTP) fold represents a novel structural motif for lipid binding/transfer and reversible membrane translocation. GLTPs transfer glycosphingolipids (GSLs) that are key regulators of cell growth, division, surface adhesion, and neurodevelopment. Herein, we report structure-guided engineering of the lipid binding features of GLTP. New crystal structures of wild-type GLTP and two mutants (D48V and A47D ||D48V), each containing bound N-nervonoyl-sulfatide, reveal the molecular basis for selective anchoring of sulfatide (3-O-sulfo-galactosylceramide) by D48V-GLTP. Directed point mutations of "portal entrance" residues, A47 and D48, reversibly regulate sphingosine access to the hydrophobic pocket via a mechanism that could involve homodimerization. "Door-opening" conformational changes by phenylalanines within the hydrophobic pocket are revealed during lipid encapsulation by new crystal structures of bona fide apo-GLTP and GLTP complexed with N-oleoyl-glucosylceramide. The development of "engineered GLTPs" with enhanced specificity for select GSLs provides a potential new therapeutic approach for targeting GSL-mediated pathologies.
PDB ID: 3RICDownload
MMDB ID: 97053
PDB Deposition Date: 2011/4/13
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 2.1  Å
Source Organism:
Similar Structures:
Biological Unit for 3RIC: dimeric; determined by author and by software (PISA)
Molecular Components in 3RIC
Label Count Molecule
Proteins (2 molecules)
2
Glycolipid Transfer Protein(Gene symbol: GLTP)
Molecule annotation
Chemicals (2 molecules)
1
2
* Click molecule labels to explore molecular sequence information.

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