1osg: Difference between revisions

Revision as of 15:21, 21 February 2008

Complex between BAFF and a BR3 derived peptide presented in a beta-hairpin scaffold

OverviewOverview

BAFF/BLyS, a member of the tumor necrosis family (TNF) superfamily of ligands, is a crucial survival factor for B cells. BAFF binds three receptors, TACI, BCMA, and BR3, with signaling through BR3 being essential for promoting B cell function. Typical TNF receptor (TNFR) family members bind their cognate ligands through interactions with two cysteine-rich domains (CRDs). However, the extracellular domain (ECD) of BR3 consists of only a partial CRD, with cysteine spacing distinct from other modules described previously. Herein, we report the solution structure of the BR3 ECD. A core region of only 19 residues adopts a stable structure in solution. The BR3 fold is analogous to the first half of a canonical TNFR CRD but is stabilized by an additional noncanonical disulfide bond. BAFF-binding determinants were identified by shotgun alanine-scanning mutagenesis of the BR3 ECD expressed on phage. Several of the key BAFF-binding residues are presented from a beta-turn that we have shown previously to be sufficient for ligand binding when transferred to a structured beta-hairpin scaffold [Kayagaki, N., Yan, M., Seshasayee, D., Wang, H., Lee, W., French, D. M., Grewal, I. S., Cochran, A. G., Gordon, N. C., Yin, J., Starovasnik, M. A, and Dixit, V. M. (2002) Immunity 10, 515-524]. Outside of the turn, mutagenesis identifies additional hydrophobic contacts that enhance the BAFF-BR3 interaction. The crystal structure of the minimal hairpin peptide, bhpBR3, in complex with BAFF reveals intimate packing of the six-residue BR3 turn into a cavity on the ligand surface. Thus, BR3 binds BAFF through a highly focused interaction site, unprecedented in the TNFR family.

About this StructureAbout this Structure

1OSG is a Single protein structure of sequence from Homo sapiens with as ligand. Full crystallographic information is available from OCA.

ReferenceReference

BAFF/BLyS receptor 3 comprises a minimal TNF receptor-like module that encodes a highly focused ligand-binding site., Gordon NC, Pan B, Hymowitz SG, Yin J, Kelley RF, Cochran AG, Yan M, Dixit VM, Fairbrother WJ, Starovasnik MA, Biochemistry. 2003 May 27;42(20):5977-83. PMID:12755599

Page seeded by OCA on Thu Feb 21 14:21:03 2008

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OCA

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-[[Image:1osg.gif|left|200px]]<br />
+[[Image:1osg.gif|left|200px]]<br /><applet load="1osg" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="1osg" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="1osg, resolution 3.00&Aring;" />
 '''Complex between BAFF and a BR3 derived peptide presented in a beta-hairpin scaffold'''<br />
 ==Overview==
-BAFF/BLyS, a member of the tumor necrosis family (TNF) superfamily of, ligands, is a crucial survival factor for B cells. BAFF binds three, receptors, TACI, BCMA, and BR3, with signaling through BR3 being essential, for promoting B cell function. Typical TNF receptor (TNFR) family members, bind their cognate ligands through interactions with two cysteine-rich, domains (CRDs). However, the extracellular domain (ECD) of BR3 consists of, only a partial CRD, with cysteine spacing distinct from other modules, described previously. Herein, we report the solution structure of the BR3, ECD. A core region of only 19 residues adopts a stable structure in, solution. The BR3 fold is analogous to the first half of a canonical TNFR, CRD but is stabilized by an additional noncanonical disulfide bond., BAFF-binding determinants were identified by shotgun alanine-scanning, mutagenesis of the BR3 ECD expressed on phage. Several of the key, BAFF-binding residues are presented from a beta-turn that we have shown, previously to be sufficient for ligand binding when transferred to a, structured beta-hairpin scaffold [Kayagaki, N., Yan, M., Seshasayee, D., Wang, H., Lee, W., French, D. M., Grewal, I. S., Cochran, A. G., Gordon, N. C., Yin, J., Starovasnik, M. A, and Dixit, V. M. (2002) Immunity 10, 515-524]. Outside of the turn, mutagenesis identifies additional, hydrophobic contacts that enhance the BAFF-BR3 interaction. The crystal, structure of the minimal hairpin peptide, bhpBR3, in complex with BAFF, reveals intimate packing of the six-residue BR3 turn into a cavity on the, ligand surface. Thus, BR3 binds BAFF through a highly focused interaction, site, unprecedented in the TNFR family.
+BAFF/BLyS, a member of the tumor necrosis family (TNF) superfamily of ligands, is a crucial survival factor for B cells. BAFF binds three receptors, TACI, BCMA, and BR3, with signaling through BR3 being essential for promoting B cell function. Typical TNF receptor (TNFR) family members bind their cognate ligands through interactions with two cysteine-rich domains (CRDs). However, the extracellular domain (ECD) of BR3 consists of only a partial CRD, with cysteine spacing distinct from other modules described previously. Herein, we report the solution structure of the BR3 ECD. A core region of only 19 residues adopts a stable structure in solution. The BR3 fold is analogous to the first half of a canonical TNFR CRD but is stabilized by an additional noncanonical disulfide bond. BAFF-binding determinants were identified by shotgun alanine-scanning mutagenesis of the BR3 ECD expressed on phage. Several of the key BAFF-binding residues are presented from a beta-turn that we have shown previously to be sufficient for ligand binding when transferred to a structured beta-hairpin scaffold [Kayagaki, N., Yan, M., Seshasayee, D., Wang, H., Lee, W., French, D. M., Grewal, I. S., Cochran, A. G., Gordon, N. C., Yin, J., Starovasnik, M. A, and Dixit, V. M. (2002) Immunity 10, 515-524]. Outside of the turn, mutagenesis identifies additional hydrophobic contacts that enhance the BAFF-BR3 interaction. The crystal structure of the minimal hairpin peptide, bhpBR3, in complex with BAFF reveals intimate packing of the six-residue BR3 turn into a cavity on the ligand surface. Thus, BR3 binds BAFF through a highly focused interaction site, unprecedented in the TNFR family.
 ==About this Structure==
-OSG is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with MG as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1OSG OCA].
+OSG is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=MG:'>MG</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1OSG OCA].
 ==Reference==
@@ Line 14: / Line 13: @@
 [[Category: Homo sapiens]]
 [[Category: Single protein]]
-[[Category: Cochran, A.G.]]
+[[Category: Cochran, A G.]]
-[[Category: Dixit, V.M.]]
+[[Category: Dixit, V M.]]
-[[Category: Fairbrother, W.J.]]
+[[Category: Fairbrother, W J.]]
-[[Category: Gordon, N.C.]]
+[[Category: Gordon, N C.]]
-[[Category: Hymowitz, S.G.]]
+[[Category: Hymowitz, S G.]]
-[[Category: Kelley, R.F.]]
+[[Category: Kelley, R F.]]
 [[Category: Pan, B.]]
-[[Category: Starovasnik, M.A.]]
+[[Category: Starovasnik, M A.]]
 [[Category: Yan, M.]]
-[[Category: Yin, J.P.]]
+[[Category: Yin, J P.]]
 [[Category: MG]]
 [[Category: beta hairpin]]
@@ Line 29: / Line 28: @@
 [[Category: protein-peptide complex]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 18:36:12 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:21:03 2008''