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Structural Characterization of Mycobacterial Phosphatidylinositol Mannoside Binding to Mouse CD1d^1,2

Dirk M. Zajonc^3,*, Gary D. Ainge, Gavin F. Painter, Wayne B. Severn and Ian A. Wilson^4,*,

^* Department of Molecular Biology and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037; and Carbohydrate Chemistry Team, Industrial Research, Gracefield Research Center, Lower Hutt, New Zealand

Mycobacterial phosphatidylinositol tetramannosides (PIM4) are agonists for a distinct population of invariant human (V24) and mouse (V14) NKT cells, when presented by CD1d. We determined the crystal structure at 2.6-Å resolution of mouse CD1d bound to a synthetic dipalmitoyl-PIM2. Natural PIM2, which differs in its fatty acid composition is a biosynthetic precursor of PIM4, PIM6, lipomannan, and lipoarabinomannan. The PIM2 headgroup (inositol-dimannoside) is the most complex to date among all the crystallized CD1d ligands and is remarkably ordered in the CD1d binding groove. A specific hydrogen-bonding network between PIM2 and CD1d orients the headgroup in the center of the binding groove and above the A' pocket. A central cluster of hydrophilic CD1d residues (Asp¹⁵³, Thr¹⁵⁶, Ser⁷⁶, Arg⁷⁹) interacts with the phosphate, inositol, and 1–6-linked mannose of the headgroup, whereas additional specificity for the 1- and 2-linked mannose is conferred by Thr¹⁵⁹. The additional two mannoses in PIM4, relative to PIM2, are located at the distal 6' carbon of the 1-6-linked mannose and would project away from the CD1d binding groove for interaction with the TCR. Compared with other CD1d-sphingolipid structures, PIM2 has an increased number of polar interactions between its headgroup and CD1, but reduced specificity for the diacylglycerol backbone. Thus, novel NKT cell agonists can be designed that focus on substitutions of the headgroup rather than on reducing lipid chain length, as in OCH and PBS-25, two potent variants of the highly stimulatory invariant NKT cell agonist -galactosylceramide.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by National Institutes of Health Grants GM62116 (to I.A.W.) and CA58896 (to I.A.W.), the Skaggs Institute for Chemical Biology (to I.A.W. and D.M.Z.), and the Marsden Fund (Royal Society of New Zealand Grant IRL0401; to G.F.P.).

² Coordinates and structure factors for the CD1d-PIM2 complex have been deposited in the Protein Data Bank (www.rcsb.org) under accession code 2GAZ.

³ Current address: La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037.

⁴ Address correspondence and reprint requests to Dr. Ian A. Wilson, Department of Molecular Biology, BCC206, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. E-mail address: wilson{at}scripps.edu

⁵ Abbreviations used in this paper: PIM, phosphatidylinositol mannoside; LM, lipomannan; LAM, lipoarabinomannan; -GalCer, -galactosylceramide; GalA-GSL, -galacturonosylceramide; PC, phosphatidylcholine; ₂M, ₂-microglobulin; i, invariant.

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