PDBsum entry: 1es7

Cytokine

PDB-id

1es7

	Biological unit* = asymmetric unit, as shown (as deduced by PQS*)


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Protein chains

Waters ×82

* Residue conservation analysis

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PDB id:

1es7

Name:

Cytokine

Title:

Complex between bmp-2 and two bmp receptor ia ectodomains

Structure:

Bone morphogenetic protein-2. Chain: a, c. Synonym: bmp-2. Engineered: yes. Bone morphogenetic protein receptor ia. Chain: b, d. Fragment: extracellular domain. Synonym: alk-3. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biological unit:

Tetramer (from PQS)

UniProt:

Chains A, C: P12643 (BMP2_HUMAN)

Seq:

Struc:


Seq:				396 a.a.

Struc:				104 a.a.

Chains B, D: P36894 (BMR1A_HUMAN)

Seq:

Struc:

Seq:

Struc:

Seq:

532 a.a.

Struc:

83 a.a.

Key:		PfamA domain
		Secondary structure			CATH domain

Enzyme class:

Chains B, D: E.C.2.7.11.30 [IntEnz] [ExPASy] [KEGG] [BRENDA]

Reaction:

ATP + [receptor-protein] = ADP + [receptor-protein] phosphate

Resolution:

2.90Å

R-factor:

0.191

R-free:

0.229

Authors:

T.Kirsch,W.Sebald,M.K.Dreyer

Key ref:

T.Kirsch et al. (2000). Crystal structure of the BMP-2-BRIA ectodomain complex.. Nat Struct Biol, 7, 492-496. [PubMed id: 10881198] [DOI: 10.1038/75903]

Date:

07-Apr-00

Release date:

07-Oct-00

Related entries:

3bmp
3bmp contains unbound bmp-2

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Key reference

DOI no: 10.1038/75903 Nat Struct Biol 7:492-496 (2000)

PubMed id: 10881198

Crystal structure of the BMP-2-BRIA ectodomain complex.

T.Kirsch, W.Sebald, M.K.Dreyer.

ABSTRACT

Bone morphogenetic proteins (BMPs) belong to the large transforming growth factor-beta (TGF-beta) superfamily of multifunctional cytokines. BMP-2 can induce ectopic bone and cartilage formation in adult vertebrates and is involved in central steps in early embryonal development in animals. Signaling by these cytokines requires binding of two types of transmembrane serine/threonine receptor kinase chains classified as type I and type II. Here we report the crystal structure of human dimeric BMP-2 in complex with two high affinity BMP receptor IA extracellular domains (BRIAec). The receptor chains bind to the 'wrist' epitopes of the BMP-2 dimer and contact both BMP-2 monomers. No contacts exist between the receptor domains. The model reveals the structural basis for discrimination between type I and type II receptors and the variability of receptor-ligand interactions that is seen in BMP-TGF-beta systems.

Selected figure(s)

Figure 1.
Figure 1. The structure of the BMP-2 -BRIA[ec] complex. a, Side view with the membrane proximal side on the bottom and b, top view approximately along the twofold axis of the complex in a ribbon representation. The BMP monomers are colored gold and blue, the two BRIA[ec] molecules are green. Secondary structure elements, chain termini and receptor loops 1 and 3 are labeled. The 'wrist' and the putative 'knuckle' epitopes on BMP-2 are highlighted. c, Stereo view of BRIA[ec] (green) superimposed with mActRII[ec] (blue). The view is onto the palm side of the hand-like structure, which provides the binding epitope for BMP-2. Disulfide bridges are depicted in yellow and magenta for BRIA[ec] and mActRII[ec], respectively, with the same numbering as in Fig. 2. The side chain of Phe 85 in helix 1 of BRIA[ec] is shown. Figure 4.
Figure 4. Stereo view of the hydrophobic pocket around BRIA[ec] residue Phe 85. Receptor residues Phe 85 -Cys 87 are depicted in green, BMP-2[A] residues Asn 59 -Val 63 in blue, and BMP-2[B] residues Trp 28 -Ile 32, Met 89 -Leu 92, and Tyr 103 -Met 106 in gold. The 2F[o] - F[c] electron density map was calculated omitting receptor helix residues 80 -87 and is contoured at 1.0 .

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (2000, 7, 492-496) copyright 2000.

Figures were selected by an automated process.

Literature references that cite this PDB file's key reference

PubMed id Reference

19762341 K.Miyazono, Y.Kamiya, and M.Morikawa (2010).
Bone morphogenetic protein receptors and signal transduction.

J Biochem, 147, 35-51.

19804412 A.Hauburger, S.von Einem, G.K.Schwaerzer, A.Buttstedt, M.Zebisch, M.Schräml, P.Hortschansky, P.Knaus, and E.Schwarz (2009).
The pro-form of BMP-2 interferes with BMP-2 signalling by competing with BMP-2 for IA receptor binding.

FEBS J, 276, 6386-6398.

19229295 A.Kotzsch, J.Nickel, A.Seher, W.Sebald, and T.D.Müller (2009).
Crystal structure analysis reveals a spring-loaded latch as molecular mechanism for GDF-5-type I receptor specificity.

EMBO J, 28, 937-947.

PDB code: 3evs

19549280 I.Tesseur, H.Zhang, W.Brecht, J.Corn, J.S.Gong, K.Yanagisawa, M.Michikawa, K.Weisgraber, Y.Huang, and T.Wyss-Coray (2009).
Bioactive TGF-beta can associate with lipoproteins and is enriched in those containing apolipoprotein E3.

J Neurochem, 110, 1254-1262.

19644449 J.N.Cash, C.A.Rejon, A.C.McPherron, D.J.Bernard, and T.B.Thompson (2009).
The structure of myostatin:follistatin 288: insights into receptor utilization and heparin binding.

EMBO J, 28, 2662-2676.

PDB code: 3hh2

19735544 K.Heinecke, A.Seher, W.Schmitz, T.D.Mueller, W.Sebald, and J.Nickel (2009).
Receptor oligomerization and beyond: a case study in bone morphogenetic proteins.

BMC Biol, 7, 59.

18485004 A.Galat, G.Gross, P.Drevet, A.Sato, and A.Ménez (2008).
Conserved structural determinants in three-fingered protein domains.

FEBS J, 275, 3207-3225.

18200552 J.Y.Lee, J.E.Choo, H.J.Park, J.B.Park, S.C.Lee, S.J.Lee, Y.J.Park, and C.P.Chung (2008).
Synthetic peptide-coated bone mineral for enhanced osteoblastic activation in vitro and in vivo.

J Biomed Mater Res A, 87, 688-697.

18768470 R.Stamler, H.T.Keutmann, Y.Sidis, C.Kattamuri, A.Schneyer, and T.B.Thompson (2008).
The Structure of FSTL3{middle dot}Activin A Complex: DIFFERENTIAL BINDING OF N-TERMINAL DOMAINS INFLUENCES FOLLISTATIN-TYPE ANTAGONIST SPECIFICITY.

J Biol Chem, 283, 32831-32838.

PDB code: 3b4v

18056265 R.V.Korupolu, U.Muenster, J.D.Read, W.Vale, and W.H.Fischer (2008).
Activin A/bone morphogenetic protein (BMP) chimeras exhibit BMP-like activity and antagonize activin and myostatin.

J Biol Chem, 283, 3782-3790.

17295905 D.Weber, A.Kotzsch, J.Nickel, S.Harth, A.Seher, U.Mueller, W.Sebald, and T.D.Mueller (2007).
A silent H-bond can be mutationally activated for high-affinity interaction of BMP-2 and activin type IIB receptor.

BMC Struct Biol, 7, 6.

PDB codes: 2h62 2h64

17483092 J.L.Zhang, Y.Huang, L.Y.Qiu, J.Nickel, and W.Sebald (2007).
von Willebrand factor type C domain-containing proteins regulate bone morphogenetic protein signaling through different recognition mechanisms.

J Biol Chem, 282, 20002-20014.

17158104 P.M.Smallwood, J.Williams, Q.Xu, D.J.Leahy, and J.Nathans (2007).
Mutational analysis of Norrin-Frizzled4 recognition.

J Biol Chem, 282, 4057-4068.

17140726 T.F.Lerch, M.Xu, T.S.Jardetzky, K.E.Mayo, I.Radhakrishnan, R.Kazer, L.D.Shea, and T.K.Woodruff (2007).
The structures that underlie normal reproductive function.

Mol Cell Endocrinol, 267, 1-5.

17409095 T.F.Lerch, S.Shimasaki, T.K.Woodruff, and T.S.Jardetzky (2007).
Structural and biophysical coupling of heparin and activin binding to follistatin isoform functions.

J Biol Chem, 282, 15930-15939.

PDB code: 2p6a

17146441 T.Shimanuki, T.Hara, T.Furuya, T.Imamura, and K.Miyazono (2007).
Modulation of the functional binding sites for TGF-beta on the type II receptor leads to suppression of TGF-beta signaling.

Oncogene, 26, 3311-3320.

17497291 Z.Duan, Q.Zheng, X.Guo, Q.Yuan, and S.Chen (2007).
Experimental research on ectopic osteogenesis of BMP2-derived peptide P24 combined with PLGA copolymers.

J Huazhong Univ Sci Technolog Med Sci, 27, 179-182.

16482217 A.E.Harrington, S.A.Morris-Triggs, B.T.Ruotolo, C.V.Robinson, S.Ohnuma, and M.Hyvönen (2006).
Structural basis for the inhibition of activin signalling by follistatin.

EMBO J, 25, 1035-1045.

PDB codes: 2arp 2arv

16550532 A.Saito, Y.Suzuki, M.Kitamura, S.Ogata, Y.Yoshihara, S.Masuda, C.Ohtsuki, and M.Tanihara (2006).
Repair of 20-mm long rabbit radial bone defects using BMP-derived peptide combined with an alpha-tricalcium phosphate scaffold.

J Biomed Mater Res A, 77, 700-706.

16606344 C.Sieber, F.Plöger, R.Schwappacher, R.Bechtold, M.Hanke, S.Kawai, Y.Muraki, M.Katsuura, M.Kimura, M.M.Rechtman, Y.I.Henis, J.Pohl, and P.Knaus (2006).
Monomeric and dimeric GDF-5 show equal type I receptor binding and oligomerization capability and have the same biological activity.

Biol Chem, 387, 451-460.

16672363 G.P.Allendorph, W.W.Vale, and S.Choe (2006).
Structure of the ternary signaling complex of a TGF-beta superfamily member.

Proc Natl Acad Sci U S A, 103, 7643-7648.

PDB code: 2goo

15844167 B.Moussian, J.Söding, H.Schwarz, and C.Nüsslein-Volhard (2005).
Retroactive, a membrane-anchored extracellular protein related to vertebrate snake neurotoxin-like proteins, is required for cuticle organization in the larva of Drosophila melanogaster.

Dev Dyn, 233, 1056-1063.

15695507 F.Hillger, G.Herr, R.Rudolph, and E.Schwarz (2005).
Biophysical comparison of BMP-2, ProBMP-2, and the free pro-peptide reveals stabilization of the pro-peptide by the mature growth factor.

J Biol Chem, 280, 14974-14980.

16480449 G.Valdimarsdottir, and C.Mummery (2005).
Functions of the TGFbeta superfamily in human embryonic stem cells.

APMIS, 113, 773-789.

15948132 H.H.Keah, and M.T.Hearn (2005).
A molecular recognition paradigm: promiscuity associated with the ligand-receptor interactions of the activin members of the TGF-beta superfamily.

J Mol Recognit, 18, 385-403.

15744518 J.Wendler, L.F.Vallejo, U.Rinas, and U.Bilitewski (2005).
Application of an SPR-based receptor assay for the determination of biologically active recombinant bone morphogenetic protein-2.

Anal Bioanal Chem, 381, 1056-1064.

15851468 M.A.Brown, Q.Zhao, K.A.Baker, C.Naik, C.Chen, L.Pukac, M.Singh, T.Tsareva, Y.Parice, A.Mahoney, V.Roschke, I.Sanyal, and S.Choe (2005).
Crystal structure of BMP-9 and functional interactions with pro-region and receptors.

J Biol Chem, 280, 25111-25118.

PDB code: 1zkz

15861141 P.Llinas, M.H.Le Du, H.Gårdsvoll, K.Danø, M.Ploug, B.Gilquin, E.A.Stura, and A.Ménez (2005).
Crystal structure of the human urokinase plasminogen activator receptor bound to an antagonist peptide.

EMBO J, 24, 1655-1663.

PDB code: 1ywh

16186117 R.W.Cook, T.B.Thompson, S.P.Kurup, T.S.Jardetzky, and T.K.Woodruff (2005).
Structural basis for a functional antagonist in the transforming growth factor beta superfamily.

J Biol Chem, 280, 40177-40186.

16129674 U.Muenster, C.A.Harrison, C.Donaldson, W.Vale, and W.H.Fischer (2005).
An activin-A/C chimera exhibits activin and myostatin antagonistic properties.

J Biol Chem, 280, 36626-36632.

16212511 X.H.Feng, and R.Derynck (2005).
Specificity and versatility in tgf-beta signaling through Smads.

Annu Rev Cell Dev Biol, 21, 659-693.

15123686 C.A.Harrison, P.C.Gray, W.H.Fischer, C.Donaldson, S.Choe, and W.Vale (2004).
An activin mutant with disrupted ALK4 binding blocks signaling via type II receptors.

J Biol Chem, 279, 28036-28044.

14996829 E.del Re, J.L.Babitt, A.Pirani, A.L.Schneyer, and H.Y.Lin (2004).
In the absence of type III receptor, the transforming growth factor (TGF)-beta type II-B receptor requires the type I receptor to bind TGF-beta2.

J Biol Chem, 279, 22765-22772.

14627550 J.P.Hanrahan, S.M.Gregan, P.Mulsant, M.Mullen, G.H.Davis, R.Powell, and S.M.Galloway (2004).
Mutations in the genes for oocyte-derived growth factors GDF9 and BMP15 are associated with both increased ovulation rate and sterility in Cambridge and Belclare sheep (Ovis aries).

Biol Reprod, 70, 900-909.

15569154 M.Sammar, S.Stricker, G.C.Schwabe, C.Sieber, A.Hartung, M.Hanke, I.Oishi, J.Pohl, Y.Minami, W.Sebald, S.Mundlos, and P.Knaus (2004).
Modulation of GDF5/BRI-b signalling through interaction with the tyrosine kinase receptor Ror2.

Genes Cells, 9, 1227-1238.

15473835 S.J.Lee (2004).
Regulation of muscle mass by myostatin.

Annu Rev Cell Dev Biol, 20, 61-86.

15064755 S.Keller, J.Nickel, J.L.Zhang, W.Sebald, and T.D.Mueller (2004).
Molecular recognition of BMP-2 and BMP receptor IA.

Nat Struct Mol Biol, 11, 481-488.

PDB codes: 1reu 1rew

15044950 V.M.Leppänen, M.M.Bespalov, P.Runeberg-Roos, U.Puurand, A.Merits, M.Saarma, and A.Goldman (2004).
The structure of GFRalpha1 domain 3 reveals new insights into GDNF binding and RET activation.

EMBO J, 23, 1452-1462.

PDB code: 1q8d

15449706 W.Sebald, J.Nickel, J.L.Zhang, and T.D.Mueller (2004).
Molecular recognition in bone morphogenetic protein (BMP)/receptor interaction.

Biol Chem, 385, 697-710.

15838109 W.Vale, E.Wiater, P.Gray, C.Harrison, L.Bilezikjian, and S.Choe (2004).
Activins and inhibins and their signaling.

Ann N Y Acad Sci, 1038, 142-147.

12665502 C.A.Harrison, P.C.Gray, S.C.Koerber, W.Fischer, and W.Vale (2003).
Identification of a functional binding site for activin on the type I receptor ALK4.

J Biol Chem, 278, 21129-21135.

14633986 D.G.Winkler, M.K.Sutherland, J.C.Geoghegan, C.Yu, T.Hayes, J.E.Skonier, D.Shpektor, M.Jonas, B.R.Kovacevich, K.Staehling-Hampton, M.Appleby, M.E.Brunkow, and J.A.Latham (2003).
Osteocyte control of bone formation via sclerostin, a novel BMP antagonist.

EMBO J, 22, 6267-6276.

12600237 F.Pohl, S.Hassel, A.Nohe, M.Flentje, P.Knaus, W.Sebald, and O.Koelbl (2003).
Radiation-induced suppression of the Bmp2 signal transduction pathway in the pluripotent mesenchymal cell line C2C12: an in vitro model for prevention of heterotopic ossification by radiotherapy.

Radiat Res, 159, 345-350.

12660162 T.B.Thompson, T.K.Woodruff, and T.S.Jardetzky (2003).
Structures of an ActRIIB:activin A complex reveal a novel binding mode for TGF-beta ligand:receptor interactions.

EMBO J, 22, 1555-1566.

PDB codes: 1nys 1nyu

12912996 T.Takada, T.Katagiri, M.Ifuku, N.Morimura, M.Kobayashi, K.Hasegawa, A.Ogamo, and R.Kamijo (2003).
Sulfated polysaccharides enhance the biological activities of bone morphogenetic proteins.

J Biol Chem, 278, 43229-43235.

12154125 B.Y.Qin, S.S.Lam, J.J.Correia, and K.Lin (2002).
Smad3 allostery links TGF-beta receptor kinase activation to transcriptional control.

Genes Dev, 16, 1950-1963.

PDB codes: 1mjs 1mk2

12221089 E.V.Bocharov, D.M.Korzhnev, M.J.Blommers, T.Arvinte, V.Y.Orekhov, M.Billeter, and A.S.Arseniev (2002).
Dynamics-modulated biological activity of transforming growth factor beta3.

J Biol Chem, 277, 46273-46279.

12478285 J.Groppe, J.Greenwald, E.Wiater, J.Rodriguez-Leon, A.N.Economides, W.Kwiatkowski, M.Affolter, W.W.Vale, J.C.Belmonte, and S.Choe (2002).
Structural basis of BMP signalling inhibition by the cystine knot protein Noggin.

Nature, 420, 636-642.

PDB code: 1m4u

12478270 J.L.Wrana (2002).
Structural biology: On the wings of inhibition.

Nature, 420, 613-614.

12485160 K.Miyazawa, M.Shinozaki, T.Hara, T.Furuya, and K.Miyazono (2002).
Two major Smad pathways in TGF-beta superfamily signalling.

Genes Cells, 7, 1191-1204.

11850637 P.J.Hart, S.Deep, A.B.Taylor, Z.Shu, C.S.Hinck, and A.P.Hinck (2002).
Crystal structure of the human TbetaR2 ectodomain--TGF-beta3 complex.

Nat Struct Biol, 9, 203-208.

PDB code: 1ktz

11880645 T.K.Bera, R.Maitra, C.Iavarone, G.Salvatore, V.Kumar, J.J.Vincent, B.K.Sathyanarayana, P.Duray, B.K.Lee, and I.Pastan (2002).
PATE, a gene expressed in prostate cancer, normal prostate, and testis, identified by a functional genomic approach.

Proc Natl Acad Sci U S A, 99, 3058-3063.

11544249 F.Docagne, N.Colloc'h, V.Bougueret, M.Page, J.Paput, M.Tripier, P.Dutartre, E.T.MacKenzie, A.Buisson, S.Komesli, and D.Vivien (2001).
A soluble transforming growth factor-beta (TGF-beta ) type I receptor mimics TGF-beta responses.

J Biol Chem, 276, 46243-46250.

11344456 H.Uludag, B.Norrie, N.Kousinioris, and T.Gao (2001).
Engineering temperature-sensitive poly(N-isopropylacrylamide) polymers as carriers of therapeutic proteins.

Biotechnol Bioeng, 73, 510-521.

11746688 P.K.Shah, C.M.Buslje, and R.Sowdhamini (2001).
Structural determinants of binding and specificity in transforming growth factor-receptor interactions.

Proteins, 45, 408-420.

11536076 X.P.Zhou, K.Woodford-Richens, R.Lehtonen, K.Kurose, M.Aldred, H.Hampel, V.Launonen, S.Virta, R.Pilarski, R.Salovaara, W.F.Bodmer, B.A.Conrad, M.Dunlop, S.V.Hodgson, T.Iwama, H.Järvinen, I.Kellokumpu, J.C.Kim, B.Leggett, D.Markie, J.P.Mecklin, K.Neale, R.Phillips, J.Piris, P.Rozen, R.S.Houlston, L.A.Aaltonen, I.P.Tomlinson, and C.Eng (2001).
Germline mutations in BMPR1A/ALK3 cause a subset of cases of juvenile polyposis syndrome and of Cowden and Bannayan-Riley-Ruvalcaba syndromes.

Am J Hum Genet, 69, 704-711.

10880444 T.Kirsch, J.Nickel, and W.Sebald (2000).
BMP-2 antagonists emerge from alterations in the low-affinity binding epitope for receptor BMPR-II.

EMBO J, 19, 3314-3324.

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 code is shown on the right.