3K48

Crystal structure of APRIL bound to a peptide

Summary for 3K48

• Entry DOI: 10.2210/pdb3k48/pdb
• Descriptor: Tumor necrosis factor ligand superfamily member 13, peptide (2 entities in total)
• Functional Keywords: cytokine, tnfsf, cleavage on pair of basic residues, disulfide bond, glycoprotein, immune response, secreted
• Biological source: Mus musculus (mouse); More
• Cellular location: Secreted (By similarity): Q9D777
• Total number of polymer chains: 6
• Total formula weight: 53208.88

Authors

Hymowitz, S.G. (deposition date: 2009-10-05, release date: 2009-11-24, Last modification date: 2024-10-30)

Primary citation

Gordon, N.C.,Lien, S.,Johnson, J.,Wallweber, H.J.,Tran, T.,Currell, B.,Mathieu, M.,Quan, C.,Starovasnik, M.A.,Hymowitz, S.G.,Kelley, R.F.
Multiple novel classes of APRIL-specific receptor-blocking peptides isolated by phage display.
J.Mol.Biol., 396:166-177, 2010

PubMed Abstract: A proliferation-inducing ligand (APRIL) is a member of the tumor necrosis factor (TNF) ligand superfamily and has a proliferative effect on both normal and tumor cells. The TNF family receptors (B-cell maturation antigen (BCMA), transmembrane activator and CAML-interactor (TACI), and BAFF receptor-3 (BR3)) for APRIL and the closely related ligand, B-cell activating factor of the TNF family (BAFF), bind these ligands through a highly conserved six residue DXL motif ((F/Y/W)-D-X-L-(V/T)-(R/G)). Panning peptide phage display libraries led to the identification of several novel classes of APRIL-binding peptides, which could be grouped by their common sequence motifs. Interestingly, only one of these ten classes consisted of peptides containing the DXL motif. Nevertheless, all classes of peptides prevented APRIL, but not BAFF, from binding BCMA, their shared receptor. Synthetic peptides based on selected sequences inhibited APRIL binding to BCMA with IC(50) values of 0.49-27 microM. An X-ray crystallographic structure of APRIL bound to one of the phage-derived peptides showed that the peptide, lacking the DXL motif, was nevertheless bound in the DXL pocket on APRIL. Our results demonstrate that even though a focused, highly conserved motif is required for APRIL-receptor interaction, remarkably, many novel and distinct classes of peptides are also capable of binding APRIL at the ligand receptor interface.

PubMed: 19945466
DOI: 10.1016/j.jmb.2009.11.041

Experimental method

X-RAY DIFFRACTION (2.8 Å)