3S0I

Crystal Structure of D48V mutant of Human Glycolipid Transfer Protein complexed with 3-O-sulfo galactosylceramide containing nervonoyl acyl chain

Summary for 3S0I

• Entry DOI: 10.2210/pdb3s0i/pdb
• Related: 1SWX 2EVT 3RIC 3RWV 3RZN 3S0K
• Descriptor: Glycolipid transfer protein, (15Z)-N-((1S,2R,3E)-2-HYDROXY-1-{[(3-O-SULFO-BETA-D-GALACTOPYRANOSYL)OXY]METHYL}HEPTADEC-3-ENYL)TETRACOS-15-ENAMIDE (3 entities in total)
• Functional Keywords: gltp-fold, transport, lipid transport
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q9NZD2
• Total number of polymer chains: 1
• Total formula weight: 24752.12

Authors

Samygina, V.,Popov, A.N.,Cabo-Bilbao, A.,Ochoa-Lizarralde, B.,Patel, D.J.,Brown, R.E.,Malinina, L. (deposition date: 2011-05-13, release date: 2012-02-08, Last modification date: 2023-09-13)

Primary citation

Samygina, V.R.,Popov, A.N.,Cabo-Bilbao, A.,Ochoa-Lizarralde, B.,Goni-de-Cerio, F.,Zhai, X.,Molotkovsky, J.G.,Patel, D.J.,Brown, R.E.,Malinina, L.
Enhanced selectivity for sulfatide by engineered human glycolipid transfer protein.
Structure, 19:1644-1654, 2011

PubMed 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.

PubMed: 22078563
DOI: 10.1016/j.str.2011.09.011

Experimental method

X-RAY DIFFRACTION (1.5 Å)