7mxh

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CD1c with antigen analogue 3CD1c with antigen analogue 3

Structural highlights

7mxh is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.11Å
Ligands:, , , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CD1C_HUMAN Antigen-presenting protein that binds self and non-self lipid and glycolipid antigens and presents them to T-cell receptors on natural killer T-cells.[1] [2] [3] [4] CD1B_HUMAN Antigen-presenting protein that binds self and non-self lipid and glycolipid antigens and presents them to T-cell receptors on natural killer T-cells.[5] [6]

Publication Abstract from PubMed

Whereas proteolytic cleavage is crucial for peptide presentation by classical major histocompatibility complex (MHC) proteins to T cells, glycolipids presented by CD1 molecules are typically presented in an unmodified form. However, the mycobacterial lipid antigen mannosyl-beta1-phosphomycoketide (MPM) may be processed through hydrolysis in antigen presenting cells, forming mannose and phosphomycoketide (PM). To further test the hypothesis that some lipid antigens are processed, and to generate antigens that lead to defined epitopes for future tuberculosis vaccines or diagnostic tests, we aimed to create hydrolysis-resistant MPM variants that retain their antigenicity. Here, we designed and tested three different, versatile synthetic strategies to chemically stabilize MPM analogs. Crystallographic studies of CD1c complexes with these three new MPM analogs showed anchoring of the lipid tail and phosphate group that is highly comparable to nature-identical MPM, with considerable conformational flexibility for the mannose head group. MPM-3, a difluoromethylene-modified version of MPM that is resistant to hydrolysis, showed altered recognition by cells, but not by CD1c proteins, supporting the cellular antigen processing hypothesis. Furthermore, the synthetic analogs elicited T cell responses that were cross-reactive with nature-identical MPM, fulfilling important requirements for future clinical use.

Rational design of a hydrolysis-resistant mycobacterial phosphoglycolipid antigen presented by CD1c to T cells.,Reijneveld JF, Marino L, Cao TP, Cheng TY, Dam D, Shahine A, Witte MD, Filippov DV, Suliman S, van der Marel GA, Moody DB, Minnaard AJ, Rossjohn J, Codee JDC, Van Rhijn I J Biol Chem. 2021 Oct;297(4):101197. doi: 10.1016/j.jbc.2021.101197. Epub 2021 , Sep 15. PMID:34536421[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Moody DB, Ulrichs T, Muhlecker W, Young DC, Gurcha SS, Grant E, Rosat JP, Brenner MB, Costello CE, Besra GS, Porcelli SA. CD1c-mediated T-cell recognition of isoprenoid glycolipids in Mycobacterium tuberculosis infection. Nature. 2000 Apr 20;404(6780):884-8. PMID:10786796 doi:http://dx.doi.org/10.1038/35009119
  2. ↑ Sugita M, van Der Wel N, Rogers RA, Peters PJ, Brenner MB. CD1c molecules broadly survey the endocytic system. Proc Natl Acad Sci U S A. 2000 Jul 18;97(15):8445-50. PMID:10890914 doi:http://dx.doi.org/10.1073/pnas.150236797
  3. ↑ Briken V, Jackman RM, Watts GF, Rogers RA, Porcelli SA. Human CD1b and CD1c isoforms survey different intracellular compartments for the presentation of microbial lipid antigens. J Exp Med. 2000 Jul 17;192(2):281-8. PMID:10899914
  4. ↑ Scharf L, Li NS, Hawk AJ, Garzon D, Zhang T, Fox LM, Kazen AR, Shah S, Haddadian EJ, Gumperz JE, Saghatelian A, Faraldo-Gomez JD, Meredith SC, Piccirilli JA, Adams EJ. The 2.5 a structure of CD1c in complex with a mycobacterial lipid reveals an open groove ideally suited for diverse antigen presentation. Immunity. 2010 Dec 14;33(6):853-62. PMID:21167756 doi:10.1016/j.immuni.2010.11.026
  5. ↑ Shamshiev A, Donda A, Prigozy TI, Mori L, Chigorno V, Benedict CA, Kappos L, Sonnino S, Kronenberg M, De Libero G. The alphabeta T cell response to self-glycolipids shows a novel mechanism of CD1b loading and a requirement for complex oligosaccharides. Immunity. 2000 Aug;13(2):255-64. PMID:10981968
  6. ↑ Winau F, Schwierzeck V, Hurwitz R, Remmel N, Sieling PA, Modlin RL, Porcelli SA, Brinkmann V, Sugita M, Sandhoff K, Kaufmann SH, Schaible UE. Saposin C is required for lipid presentation by human CD1b. Nat Immunol. 2004 Feb;5(2):169-74. Epub 2004 Jan 11. PMID:14716313 doi:10.1038/ni1035
  7. ↑ Reijneveld JF, Marino L, Cao TP, Cheng TY, Dam D, Shahine A, Witte MD, Filippov DV, Suliman S, van der Marel GA, Moody DB, Minnaard AJ, Rossjohn J, Codée JDC, Van Rhijn I. Rational design of a hydrolysis-resistant mycobacterial phosphoglycolipid antigen presented by CD1c to T cells. J Biol Chem. 2021 Oct;297(4):101197. PMID:34536421 doi:10.1016/j.jbc.2021.101197

7mxh, resolution 2.11Å

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