 |
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
|
PDB id:
|
|
|
|
| Name: |
|
Cytokine
|
|
|
Title:
|
|
Crystal structure of trance/rankl cytokine.
|
|
Structure:
|
|
Tumor necrosis factor ligand superfamily member 11. Chain: x, y, z. Fragment: c-terminal receptor-binding ectodomain, residues 156-316. Synonym: tnf-related activation-induced cytokine, trance, receptor activator of nf-kappa-b ligand, rankl, osteoclast differentiation factor, odf, osteoprotegerin ligand, opgl, tnfsf11.
|
|
Source:
|
|
Mus musculus. House mouse. Organism_taxid: 10090. Gene: rankl. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
|
|
Biol. unit:
|
|
Trimer (from
)
|
|
Resolution:
|
|
|
2.60Å
|
R-factor:
|
0.235
|
R-free:
|
0.286
|
|
|
Authors:
|
|
C.A.Nelson,D.H.Fremont
|
|
Key ref:
|
|
J.Lam
et al.
(2001).
Crystal structure of the TRANCE/RANKL cytokine reveals determinants of receptor-ligand specificity.
J Clin Invest,
108,
971-979.
PubMed id:
Ref:
|
|
|
Date:
|
|
|
23-Aug-01
|
Release date:
|
12-Sep-01
|
|
|
|
|
|
|
PROCHECK
|
|
|
|
|
|
Headers
|
|
|
|
References
|
|
|
|
|
|
|
|
|
|
|
|
O35235
(TNF11_MOUSE) -
Tumor necrosis factor ligand superfamily member 11
|
|
|
|
Seq:
Struc:
|
|
|
|
316 a.a.
155 a.a.
|
|
|
|
|
|
|
|
|
|
|
|
|
Key: |
 |
PfamA domain |
|
|
 |
Secondary structure |
|
 |
CATH domain |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Gene Ontology (GO) functional annotation
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Cellular component
|
membrane
|
1 term
|
|
|
Biological process
|
immune response
|
1 term
|
|
|
Biochemical function
|
tumor necrosis factor receptor binding
|
1 term
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
|
J Clin Invest
108:971-979
(2001)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
Crystal structure of the TRANCE/RANKL cytokine reveals determinants of receptor-ligand specificity.
|
|
J.Lam,
C.A.Nelson,
F.P.Ross,
S.L.Teitelbaum,
D.H.Fremont.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
RANK, the receptor activator of NF-kappaB, and its ligand RANKL (initially
termed TRANCE, also termed ODF and OPGL), are a TNF superfamily receptor-ligand
pair that govern the development and function of osteoclasts, lymphoid tissue,
and mammary epithelium. While TNF family cytokines share a common structural
scaffold, individual receptor-ligand pairs associate with high specificity.
Given the low level of amino acid conservation among members of the TNF
superfamily, the means by which these molecules achieve specificity cannot be
completely understood without knowledge of their three-dimensional structures.
To determine the elements of RANKL that mediate RANK activation, we have
crystallized the ectodomain of murine RANKL and solved its structure to a
resolution of 2.6 A. RANKL self-associates as a homotrimer with four unique
surface loops that distinguish it from other TNF family cytokines. Mutagenesis
of selected residues in these loops significantly modulates RANK activation, as
evidenced by in vitro osteoclastogenesis, thereby establishing their necessity
in mediating the biological activities of RANKL. Such structural determinants of
RANKL-RANK specificity may be of relevance in the pharmacologic design of
compounds to ameliorate osteopenic disorders of bone.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Literature references that cite this PDB file's key reference
|
|
|
| |
PubMed id
|
|
Reference
|
|
|
|
|
|
J.C.Crockett,
D.J.Mellis,
D.I.Scott,
and
M.H.Helfrich
(2011).
New knowledge on critical osteoclast formation and activation pathways from study of rare genetic diseases of osteoclasts: focus on the RANK/RANKL axis.
|
| |
Osteoporos Int, 22,
1.
|
|
|
|
|
|
|
S.S.Baloul,
L.C.Gerstenfeld,
E.F.Morgan,
R.S.Carvalho,
T.E.Van Dyke,
and
A.Kantarci
(2011).
Mechanism of action and morphologic changes in the alveolar bone in response to selective alveolar decortication-facilitated tooth movement.
|
| |
Am J Orthod Dentofacial Orthop, 139,
S83-101.
|
|
|
|
|
|
|
Z.Wang,
and
L.K.McCauley
(2011).
Osteoclasts and odontoclasts: signaling pathways to development and disease.
|
| |
Oral Dis, 17,
129-142.
|
|
|
|
|
|
|
H.M.Ta,
G.T.Nguyen,
H.M.Jin,
J.Choi,
H.Park,
N.Kim,
H.Y.Hwang,
and
K.K.Kim
(2010).
Structure-based development of a receptor activator of nuclear factor-kappaB ligand (RANKL) inhibitor peptide and molecular basis for osteopetrosis.
|
| |
Proc Natl Acad Sci U S A, 107,
20281-20286.
|
|
|
PDB codes:
|
|
|
|
|
|
|
|
I.Kramer,
C.Halleux,
H.Keller,
M.Pegurri,
J.H.Gooi,
P.B.Weber,
J.Q.Feng,
L.F.Bonewald,
and
M.Kneissel
(2010).
Osteocyte Wnt/beta-catenin signaling is required for normal bone homeostasis.
|
| |
Mol Cell Biol, 30,
3071-3085.
|
|
|
|
|
|
|
R.Hanada,
T.Hanada,
and
J.M.Penninger
(2010).
Physiology and pathophysiology of the RANKL/RANK system.
|
| |
Biol Chem, 391,
1365-1370.
|
|
|
|
|
|
|
H.L.Wright,
H.S.McCarthy,
J.Middleton,
and
M.J.Marshall
(2009).
RANK, RANKL and osteoprotegerin in bone biology and disease.
|
| |
Curr Rev Musculoskelet Med, 2,
56-64.
|
|
|
|
|
|
|
A.Leibbrandt,
and
J.M.Penninger
(2008).
RANK/RANKL: regulators of immune responses and bone physiology.
|
| |
Ann N Y Acad Sci, 1143,
123-150.
|
|
|
|
|
|
|
G.E.Beranger,
D.Momier,
N.Rochet,
G.F.Carle,
and
J.C.Scimeca
(2008).
Poly(adp-ribose) polymerase-1 regulates Tracp gene promoter activity during RANKL-induced osteoclastogenesis.
|
| |
J Bone Miner Res, 23,
564-571.
|
|
|
|
|
|
|
K.Yasunori,
T.Masaaki,
N.Tetsuyuki,
K.Hayato,
and
N.Akira
(2008).
Reduction of urinary levels of pyridinoline and deoxypyridinoline and serum levels of soluble receptor activator of NF-kappaB ligand by etanercept in patients with rheumatoid arthritis.
|
| |
Clin Rheumatol, 27,
1093-1101.
|
|
|
|
|
|
|
S.Ganguly,
L.A.Ashley,
C.M.Pendleton,
R.D.Grey,
G.C.Howard,
L.D.Castle,
D.K.Peyton,
M.E.Fultz,
and
D.L.DeMoss
(2008).
Characterization of osteoblastic properties of 7F2 and UMR-106 cultures after acclimation to reduced levels of fetal bovine serum.
|
| |
Can J Physiol Pharmacol, 86,
403-415.
|
|
|
|
|
|
|
C.Sobacchi,
A.Frattini,
M.M.Guerrini,
M.Abinun,
A.Pangrazio,
L.Susani,
R.Bredius,
G.Mancini,
A.Cant,
N.Bishop,
P.Grabowski,
A.Del Fattore,
C.Messina,
G.Errigo,
F.P.Coxon,
D.I.Scott,
A.Teti,
M.J.Rogers,
P.Vezzoni,
A.Villa,
and
M.H.Helfrich
(2007).
Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL.
|
| |
Nat Genet, 39,
960-962.
|
|
|
|
|
|
|
G.E.Beranger,
D.Momier,
J.M.Guigonis,
M.Samson,
G.F.Carle,
and
J.C.Scimeca
(2007).
Differential binding of poly(ADP-Ribose) polymerase-1 and JunD/Fra2 accounts for RANKL-induced Tcirg1 gene expression during osteoclastogenesis.
|
| |
J Bone Miner Res, 22,
975-983.
|
|
|
|
|
|
|
S.L.Teitelbaum
(2007).
Osteoclasts: what do they do and how do they do it?
|
| |
Am J Pathol, 170,
427-435.
|
|
|
|
|
|
|
S.X.Qiu,
C.Dan,
L.S.Ding,
S.Peng,
S.N.Chen,
N.R.Farnsworth,
J.Nolta,
M.L.Gross,
and
P.Zhou
(2007).
A triterpene glycoside from black cohosh that inhibits osteoclastogenesis by modulating RANKL and TNFalpha signaling pathways.
|
| |
Chem Biol, 14,
860-869.
|
|
|
|
|
|
|
K.Aoki,
H.Saito,
C.Itzstein,
M.Ishiguro,
T.Shibata,
R.Blanque,
A.H.Mian,
M.Takahashi,
Y.Suzuki,
M.Yoshimatsu,
A.Yamaguchi,
P.Deprez,
P.Mollat,
R.Murali,
K.Ohya,
W.C.Horne,
and
R.Baron
(2006).
A TNF receptor loop peptide mimic blocks RANK ligand-induced signaling, bone resorption, and bone loss.
|
| |
J Clin Invest, 116,
1525-1534.
|
|
|
|
|
|
|
S.L.Teitelbaum
(2006).
Osteoclasts; culprits in inflammatory osteolysis.
|
| |
Arthritis Res Ther, 8,
201.
|
|
|
|
|
|
|
D.A.Dossing,
and
P.H.Stern
(2005).
Receptor activator of NF-kappaB ligand protein expression in UMR-106 cells is differentially regulated by parathyroid hormone and calcitriol.
|
| |
J Cell Biochem, 95,
1029-1041.
|
|
|
|
|
|
|
N.A.Sims,
B.J.Jenkins,
A.Nakamura,
J.M.Quinn,
R.Li,
M.T.Gillespie,
M.Ernst,
L.Robb,
and
T.J.Martin
(2005).
Interleukin-11 receptor signaling is required for normal bone remodeling.
|
| |
J Bone Miner Res, 20,
1093-1102.
|
|
|
|
|
|
|
S.Bai,
H.Kitaura,
H.Zhao,
J.Chen,
J.M.Müller,
R.Schüle,
B.Darnay,
D.V.Novack,
F.P.Ross,
and
S.L.Teitelbaum
(2005).
FHL2 inhibits the activated osteoclast in a TRAF6-dependent manner.
|
| |
J Clin Invest, 115,
2742-2751.
|
|
|
|
|
|
|
C.T.Gange,
J.M.Quinn,
H.Zhou,
V.Kartsogiannis,
M.T.Gillespie,
and
K.W.Ng
(2004).
Characterization of sugar binding by osteoclast inhibitory lectin.
|
| |
J Biol Chem, 279,
29043-29049.
|
|
|
|
|
|
|
G.Zhang
(2004).
Tumor necrosis factor family ligand-receptor binding.
|
| |
Curr Opin Struct Biol, 14,
154-160.
|
|
|
|
|
|
|
K.D.Häusler,
N.J.Horwood,
Y.Chuman,
J.L.Fisher,
J.Ellis,
T.J.Martin,
J.S.Rubin,
and
M.T.Gillespie
(2004).
Secreted frizzled-related protein-1 inhibits RANKL-dependent osteoclast formation.
|
| |
J Bone Miner Res, 19,
1873-1881.
|
|
|
|
|
|
|
N.A.Sims,
B.J.Jenkins,
J.M.Quinn,
A.Nakamura,
M.Glatt,
M.T.Gillespie,
M.Ernst,
and
T.J.Martin
(2004).
Glycoprotein 130 regulates bone turnover and bone size by distinct downstream signaling pathways.
|
| |
J Clin Invest, 113,
379-389.
|
|
|
|
|
|
|
S.Kwan Tat,
M.Padrines,
S.Théoleyre,
D.Heymann,
and
Y.Fortun
(2004).
IL-6, RANKL, TNF-alpha/IL-1: interrelations in bone resorption pathophysiology.
|
| |
Cytokine Growth Factor Rev, 15,
49-60.
|
|
|
|
|
|
|
S.L.Teitelbaum
(2004).
RANKing c-Jun in osteoclast development.
|
| |
J Clin Invest, 114,
463-465.
|
|
|
|
|
|
|
S.Theoleyre,
Y.Wittrant,
S.K.Tat,
Y.Fortun,
F.Redini,
and
D.Heymann
(2004).
The molecular triad OPG/RANK/RANKL: involvement in the orchestration of pathophysiological bone remodeling.
|
| |
Cytokine Growth Factor Rev, 15,
457-475.
|
|
|
|
|
|
|
T.Mori,
A.Oguro,
T.Ohtsu,
and
Y.Nakamura
(2004).
RNA aptamers selected against the receptor activator of NF-kappaB acquire general affinity to proteins of the tumor necrosis factor receptor family.
|
| |
Nucleic Acids Res, 32,
6120-6128.
|
|
|
|
|
|
|
X.Cheng,
M.Kinosaki,
M.Takami,
Y.Choi,
H.Zhang,
and
R.Murali
(2004).
Disabling of receptor activator of nuclear factor-kappaB (RANK) receptor complex by novel osteoprotegerin-like peptidomimetics restores bone loss in vivo.
|
| |
J Biol Chem, 279,
8269-8277.
|
|
|
|
|
|
|
A.L.Gavin,
D.Aït-Azzouzene,
C.F.Ware,
and
D.Nemazee
(2003).
DeltaBAFF, an alternate splice isoform that regulates receptor binding and biopresentation of the B cell survival cytokine, BAFF.
|
| |
J Biol Chem, 278,
38220-38228.
|
|
|
|
|
|
|
E.M.Sordillo,
and
R.N.Pearse
(2003).
RANK-Fc: a therapeutic antagonist for RANK-L in myeloma.
|
| |
Cancer, 97,
802-812.
|
|
|
|
|
|
|
M.M.Roberts,
A.R.Coker,
G.Fossati,
P.Mascagni,
A.R.Coates,
and
S.P.Wood
(2003).
Mycobacterium tuberculosis chaperonin 10 heptamers self-associate through their biologically active loops.
|
| |
J Bacteriol, 185,
4172-4185.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
M.Zaidi,
H.C.Blair,
B.S.Moonga,
E.Abe,
and
C.L.Huang
(2003).
Osteoclastogenesis, bone resorption, and osteoclast-based therapeutics.
|
| |
J Bone Miner Res, 18,
599-609.
|
|
|
|
|
|
|
T.Ikeda,
M.Kasai,
J.Suzuki,
H.Kuroyama,
S.Seki,
M.Utsuyama,
and
K.Hirokawa
(2003).
Multimerization of the receptor activator of nuclear factor-kappaB ligand (RANKL) isoforms and regulation of osteoclastogenesis.
|
| |
J Biol Chem, 278,
47217-47222.
|
|
|
|
|
|
|
W.Huang,
R.J.O'Keefe,
and
E.M.Schwarz
(2003).
Exposure to receptor-activator of NFkappaB ligand renders pre-osteoclasts resistant to IFN-gamma by inducing terminal differentiation.
|
| |
Arthritis Res Ther, 5,
R49-R59.
|
|
|
|
|
|
|
Y.Liu,
X.Hong,
J.Kappler,
L.Jiang,
R.Zhang,
L.Xu,
C.H.Pan,
W.E.Martin,
R.C.Murphy,
H.B.Shu,
S.Dai,
and
G.Zhang
(2003).
Ligand-receptor binding revealed by the TNF family member TALL-1.
|
| |
Nature, 423,
49-56.
|
|
|
PDB codes:
|
|
|
|
|
|
|
|
A.Ashkenazi
(2002).
Targeting death and decoy receptors of the tumour-necrosis factor superfamily.
|
| |
Nat Rev Cancer, 2,
420-430.
|
|
|
|
|
|
|
D.A.Oren,
Y.Li,
Y.Volovik,
T.S.Morris,
C.Dharia,
K.Das,
O.Galperina,
R.Gentz,
and
E.Arnold
(2002).
Structural basis of BLyS receptor recognition.
|
| |
Nat Struct Biol, 9,
288-292.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
E.M.Gravallese
(2002).
Bone destruction in arthritis.
|
| |
Ann Rheum Dis, 61,
ii84-ii86.
|
|
|
|
|
|
|
J.Lam,
Y.Abu-Amer,
C.A.Nelson,
D.H.Fremont,
F.P.Ross,
and
S.L.Teitelbaum
(2002).
Tumour necrosis factor superfamily cytokines and the pathogenesis of inflammatory osteolysis.
|
| |
Ann Rheum Dis, 61,
ii82-ii83.
|
|
|
|
|
|
The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
|
|
Links
