3lkj

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Template:STRUCTURE 3lkj

Contents

Small Molecule Inhibition of the TNF Family Cyokine CD40 Ligand Through a Subunit Fracture Mechanism

Template:ABSTRACT PUBMED 21417339

Disease

[CD40L_HUMAN] Defects in CD40LG are the cause of X-linked immunodeficiency with hyper-IgM type 1 (HIGM1) [MIM:308230]; also known as X-linked hyper IgM syndrome (XHIM). HIGM1 is an immunoglobulin isotype switch defect characterized by elevated concentrations of serum IgM and decreased amounts of all other isotypes. Affected males present at an early age (usually within the first year of life) recurrent bacterial and opportunistic infections, including Pneumocystis carinii pneumonia and intractable diarrhea due to cryptosporidium infection. Despite substitution treatment with intravenous immunoglobulin, the overall prognosis is rather poor, with a death rate of about 10% before adolescence.[1][2][3][4][5][6][7][8][9][10]

Function

[CD40L_HUMAN] Mediates B-cell proliferation in the absence of co-stimulus as well as IgE production in the presence of IL-4. Involved in immunoglobulin class switching.[11] Release of soluble CD40L from platelets is partially regulated by GP IIb/IIIa, actin polymerization, and an matrix metalloproteinases (MMP) inhibitor-sensitive pathway.[12]

About this Structure

3lkj is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

  • Silvian LF, Friedman JE, Strauch K, Cachero TG, Day ES, Qian F, Cunningham B, Fung A, Sun L, Su L, Zheng Z, Kumaravel G, Whitty A. Small Molecule Inhibition of the TNF Family Cytokine CD40 Ligand through a Subunit Fracture Mechanism. ACS Chem Biol. 2011 Jun 17;6(6):636-47. Epub 2011 Apr 20. PMID:21417339 doi:10.1021/cb2000346
  1. ↑ Aruffo A, Farrington M, Hollenbaugh D, Li X, Milatovich A, Nonoyama S, Bajorath J, Grosmaire LS, Stenkamp R, Neubauer M, et al.. The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome. Cell. 1993 Jan 29;72(2):291-300. PMID:7678782
  2. ↑ Korthauer U, Graf D, Mages HW, Briere F, Padayachee M, Malcolm S, Ugazio AG, Notarangelo LD, Levinsky RJ, Kroczek RA. Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM. Nature. 1993 Feb 11;361(6412):539-41. PMID:7679206 doi:http://dx.doi.org/10.1038/361539a0
  3. ↑ DiSanto JP, Bonnefoy JY, Gauchat JF, Fischer A, de Saint Basile G. CD40 ligand mutations in x-linked immunodeficiency with hyper-IgM. Nature. 1993 Feb 11;361(6412):541-3. PMID:8094231 doi:http://dx.doi.org/10.1038/361541a0
  4. ↑ Allen RC, Armitage RJ, Conley ME, Rosenblatt H, Jenkins NA, Copeland NG, Bedell MA, Edelhoff S, Disteche CM, Simoneaux DK, et al.. CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome. Science. 1993 Feb 12;259(5097):990-3. PMID:7679801
  5. ↑ Macchi P, Villa A, Strina D, Sacco MG, Morali F, Brugnoni D, Giliani S, Mantuano E, Fasth A, Andersson B, et al.. Characterization of nine novel mutations in the CD40 ligand gene in patients with X-linked hyper IgM syndrome of various ancestry. Am J Hum Genet. 1995 Apr;56(4):898-906. PMID:7717401
  6. ↑ Saiki O, Tanaka T, Wada Y, Uda H, Inoue A, Katada Y, Izeki M, Iwata M, Nunoi H, Matsuda I, et al.. Signaling through CD40 rescues IgE but not IgG or IgA secretion in X-linked immunodeficiency with hyper-IgM. J Clin Invest. 1995 Feb;95(2):510-4. PMID:7532185 doi:http://dx.doi.org/10.1172/JCI117692
  7. ↑ Katz F, Hinshelwood S, Rutland P, Jones A, Kinnon C, Morgan G. Mutation analysis in CD40 ligand deficiency leading to X-linked hypogammaglobulinemia with hyper IgM syndrome. Hum Mutat. 1996;8(3):223-8. PMID:8889581 doi:<223::AID-HUMU5>3.0.CO;2-A 10.1002/(SICI)1098-1004(1996)8:3<223::AID-HUMU5>3.0.CO;2-A
  8. ↑ Lin Q, Rohrer J, Allen RC, Larche M, Greene JM, Shigeoka AO, Gatti RA, Derauf DC, Belmont JW, Conley ME. A single strand conformation polymorphism study of CD40 ligand. Efficient mutation analysis and carrier detection for X-linked hyper IgM syndrome. J Clin Invest. 1996 Jan 1;97(1):196-201. PMID:8550833 doi:http://dx.doi.org/10.1172/JCI118389
  9. ↑ Nonoyama S, Shimadzu M, Toru H, Seyama K, Nunoi H, Neubauer M, Yata J, Och HD. Mutations of the CD40 ligand gene in 13 Japanese patients with X-linked hyper-IgM syndrome. Hum Genet. 1997 May;99(5):624-7. PMID:9150729
  10. ↑ Seyama K, Nonoyama S, Gangsaas I, Hollenbaugh D, Pabst HF, Aruffo A, Ochs HD. Mutations of the CD40 ligand gene and its effect on CD40 ligand expression in patients with X-linked hyper IgM syndrome. Blood. 1998 Oct 1;92(7):2421-34. PMID:9746782
  11. ↑ Furman MI, Krueger LA, Linden MD, Barnard MR, Frelinger AL 3rd, Michelson AD. Release of soluble CD40L from platelets is regulated by glycoprotein IIb/IIIa and actin polymerization. J Am Coll Cardiol. 2004 Jun 16;43(12):2319-25. PMID:15193700 doi:10.1016/j.jacc.2003.12.055
  12. ↑ Furman MI, Krueger LA, Linden MD, Barnard MR, Frelinger AL 3rd, Michelson AD. Release of soluble CD40L from platelets is regulated by glycoprotein IIb/IIIa and actin polymerization. J Am Coll Cardiol. 2004 Jun 16;43(12):2319-25. PMID:15193700 doi:10.1016/j.jacc.2003.12.055

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