3S0K

Crystal Structure of Human Glycolipid Transfer Protein complexed with glucosylceramide containing oleoyl acyl chain (18:1)

Summary for 3S0K

• Entry DOI: 10.2210/pdb3s0k/pdb
• Related: 1SWX 2EUK 3RIC 3RWV 3RZN
• Descriptor: Glycolipid transfer protein, (9Z)-N-[(2S,3R,4E)-1-(beta-D-glucopyranosyloxy)-3-hydroxyoctadec-4-en-2-yl]octadec-9-enamide, NICKEL (II) ION, ... (4 entities in total)
• Functional Keywords: gltp-fold, lipid transport
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q9NZD2
• Total number of polymer chains: 1
• Total formula weight: 24662.55

Authors

Cabo-Bilbao, A.,Samygina, V.,Popov, A.N.,Ochoa-Lizarralde, B.,Goni-de-Cerio, F.,Patel, D.J.,Brown, R.E.,Malinina, L. (deposition date: 2011-05-13, release date: 2012-02-08, Last modification date: 2024-02-28)

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 (1.4 Å)