PDBsum entry 1lxi

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Hormone/growth factor PDB id
Protein chain
104 a.a. *
Waters ×71
* Residue conservation analysis
PDB id:
Name: Hormone/growth factor
Title: Refinement of bmp7 crystal structure
Structure: Bone morphogenetic protein 7. Chain: a. Synonym: bmp7, osteogenic protein 1, op-1. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: bmp7. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_cell: ovary cells. Other_details: dhfr-
Biol. unit: Dimer (from PDB file)
2.00Å     R-factor:   0.229     R-free:   0.244
Authors: J.Greenwald,J.Groppe,W.Kwiatkowski,S.Choe
Key ref:
J.Greenwald et al. (2003). The BMP7/ActRII extracellular domain complex provides new insights into the cooperative nature of receptor assembly. Mol Cell, 11, 605-617. PubMed id: 12667445 DOI: 10.1016/S1097-2765(03)00094-7
05-Jun-02     Release date:   01-Apr-03    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P18075  (BMP7_HUMAN) -  Bone morphogenetic protein 7
431 a.a.
104 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   1 term 
  Biochemical function     growth factor activity     1 term  


DOI no: 10.1016/S1097-2765(03)00094-7 Mol Cell 11:605-617 (2003)
PubMed id: 12667445  
The BMP7/ActRII extracellular domain complex provides new insights into the cooperative nature of receptor assembly.
J.Greenwald, J.Groppe, P.Gray, E.Wiater, W.Kwiatkowski, W.Vale, S.Choe.
Activins and bone morphogenetic proteins (BMPs) elicit diverse biological responses by signaling through two pairs of structurally related type I and type II receptors. Here we report the crystal structure of BMP7 in complex with the extracellular domain (ECD) of the activin type II receptor. Our structure produces a compelling four-receptor model, revealing that the types I and II receptor ECDs make no direct contacts. Nevertheless, we find that truncated receptors lacking their cytoplasmic domain retain the ability to cooperatively assemble in the cell membrane. Also, the affinity of BMP7 for its low-affinity type I receptor ECD increases 5-fold in the presence of its type II receptor ECD. Taken together, our results provide a view of the ligand-mediated cooperative assembly of BMP and activin receptors that does not rely on receptor-receptor contacts.
  Selected figure(s)  
Figure 1.
Figure 1. The Structure of the BMP7/ActRII-ECD Complex(A and B) Ribbon diagrams of the BMP7/ActRII-ECD complex (A) with the 2-fold symmetry axis vertical and the membrane facing side at the bottom and (B) the view from above (BMP7, gold and rust; ActRII-ECD, green; cystine sulfurs, yellow space-filling).(C) Stereo view of the interface between BMP7 and ActRII in an orientation close to (A). The residues within 4 Å of the binding partner as well as Glu29 are displayed as balls and sticks. Glu29 and those residues whose mutations are known to affect binding (pink, Figure 2) are labeled.In (A)–(C) significant conformational changes are highlighted (dark blue), and in (C) they are overlaid with the unbound conformations (light blue). This figure was made using MOLSCRIPT (Kraulis, 1991).
Figure 3.
Figure 3. The Model of the BMP7/ActRII/BMPRIa Six-Chain Signaling ComplexBMPRIa (purple) was placed in the complex by aligning the BMP2/BMPRIa structure (Kirsch et al., 2000a) with BMP7.(A) Side view as in Figure 1A is shown as a solvent accessible surface. The horizontal line represents the plane of the membrane.(B) Bottom view (opposite from Figure 1B). Sugars are in black. The C termini are marked with yellow dots and the horizontal distances between them as projected onto the plane of the membrane are 83 Å for type II-type II, 66 Å for type I-type I, and 27 Å and 68 Å for type I-type II. (A) and (B) were prepared with DINO (Philippsen, 2001).(C) Stereo view of ActRII and TGF-βRII bound to their respective ligands overlaid with the BMP2/BMPRIa structure. The BMP7/ActRII complex was aligned as in (A) using the entire ligand. In order to overlay the TGF-βRII binding site (tip of finger 2 on TGF-β3) with BMP2, only 14 residues (86–92 and 98–104 of BMP2) were used for the alignment (Hart et al., 2002). The color scheme is BMP2, white; BMP7, gold; ActRII, green; TGF-β3, blue; TGF-βRII, red; BMPRIa, purple. The receptors and their C termini are labeled.
  The above figures are reprinted by permission from Cell Press: Mol Cell (2003, 11, 605-617) copyright 2003.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
22992590 J.Massagué (2012).
TGFβ signalling in context.
  Nat Rev Mol Cell Biol, 13, 616-630.  
20545624 C.C.Rider, and B.Mulloy (2010).
Bone morphogenetic protein and growth differentiation factor cytokine families and their protein antagonists.
  Biochem J, 429, 1.  
20674464 J.W.Lowery, and Caestecker (2010).
BMP signaling in vascular development and disease.
  Cytokine Growth Factor Rev, 21, 287-298.  
19762341 K.Miyazono, Y.Kamiya, and M.Morikawa (2010).
Bone morphogenetic protein receptors and signal transduction.
  J Biochem, 147, 35-51.  
20629020 L.Calvanese, D.Marasco, N.Doti, A.Saporito, G.D'Auria, L.Paolillo, M.Ruvo, and L.Falcigno (2010).
Structural investigations on the Nodal-Cripto binding: a theoretical and experimental approach.
  Biopolymers, 93, 1011-1021.  
  20927405 S.Harth, A.Kotzsch, J.Hu, W.Sebald, and T.D.Mueller (2010).
A selection fit mechanism in BMP receptor IA as a possible source for BMP ligand-receptor promiscuity.
  PLoS One, 5, 0.
PDB code: 3nh7
20704570 T.Liu, and X.H.Feng (2010).
Regulation of TGF-beta signalling by protein phosphatases.
  Biochem J, 430, 191-198.  
20861306 W.J.Kuo, M.A.Digman, and A.D.Lander (2010).
Heparan sulfate acts as a bone morphogenetic protein coreceptor by facilitating ligand-induced receptor hetero-oligomerization.
  Mol Biol Cell, 21, 4028-4041.  
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
19897402 C.Sieber, J.Kopf, C.Hiepen, and P.Knaus (2009).
Recent advances in BMP receptor signaling.
  Cytokine Growth Factor Rev, 20, 343-355.  
19553149 E.Roessler, W.Pei, M.V.Ouspenskaia, J.D.Karkera, J.I.Veléz, S.Banerjee-Basu, G.Gibney, P.J.Lupo, L.E.Mitchell, J.A.Towbin, P.Bowers, J.W.Belmont, E.Goldmuntz, A.D.Baxevanis, B.Feldman, and M.Muenke (2009).
Cumulative ligand activity of NODAL mutations and modifiers are linked to human heart defects and holoprosencephaly.
  Mol Genet Metab, 98, 225-234.  
19161338 J.Baardsnes, C.S.Hinck, A.P.Hinck, and M.D.O'Connor-McCourt (2009).
TbetaR-II discriminates the high- and low-affinity TGF-beta isoforms via two hydrogen-bonded ion pairs.
  Biochemistry, 48, 2146-2155.  
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
19926516 J.Nickel, W.Sebald, J.C.Groppe, and T.D.Mueller (2009).
Intricacies of BMP receptor assembly.
  Cytokine Growth Factor Rev, 20, 367-377.  
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.  
19424823 K.P.Holbourn, B.Perbal, and K.Ravi Acharya (2009).
Proteins on the catwalk: modelling the structural domains of the CCN family of proteins.
  J Cell Commun Signal, 3, 25-41.  
19910235 M.H.Alaoui-Ismaili, and D.Falb (2009).
Design of second generation therapeutic recombinant bone morphogenetic proteins.
  Cytokine Growth Factor Rev, 20, 501-507.  
19876372 M.Sikora, J.I.Sułkowska, and M.Cieplak (2009).
Mechanical strength of 17,134 model proteins and cysteine slipknots.
  PLoS Comput Biol, 5, e1000547.  
19195913 R.A.Andhare, N.Takahashi, W.Knudson, and C.B.Knudson (2009).
Hyaluronan promotes the chondrocyte response to BMP-7.
  Osteoarthritis Cartilage, 17, 906-916.  
19377468 S.C.Little, and M.C.Mullins (2009).
Bone morphogenetic protein heterodimers assemble heteromeric type I receptor complexes to pattern the dorsoventral axis.
  Nat Cell Biol, 11, 637-643.  
19900832 S.Vukicevic, and L.Grgurevic (2009).
BMP-6 and mesenchymal stem cell differentiation.
  Cytokine Growth Factor Rev, 20, 441-448.  
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.  
18160401 A.Kotzsch, J.Nickel, A.Seher, K.Heinecke, L.van Geersdaele, T.Herrmann, W.Sebald, and T.D.Mueller (2008).
Structure analysis of bone morphogenetic protein-2 type I receptor complexes reveals a mechanism of receptor inactivation in juvenile polyposis syndrome.
  J Biol Chem, 283, 5876-5887.
PDB codes: 2qj9 2qja 2qjb
18621057 G.Sengle, R.N.Ono, K.M.Lyons, H.P.Bächinger, and L.Y.Sakai (2008).
A new model for growth factor activation: type II receptors compete with the prodomain for BMP-7.
  J Mol Biol, 381, 1025-1039.  
18243111 J.Groppe, C.S.Hinck, P.Samavarchi-Tehrani, C.Zubieta, J.P.Schuermann, A.B.Taylor, P.M.Schwarz, J.L.Wrana, and A.P.Hinck (2008).
Cooperative assembly of TGF-beta superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor binding.
  Mol Cell, 29, 157-168.
PDB code: 2pjy
18243107 J.Massagué (2008).
A very private TGF-beta receptor embrace.
  Mol Cell, 29, 149-150.  
18789696 K.P.Holbourn, K.R.Acharya, and B.Perbal (2008).
The CCN family of proteins: structure-function relationships.
  Trends Biochem Sci, 33, 461-473.  
18042551 P.B.Yu, D.Y.Deng, H.Beppu, C.C.Hong, C.Lai, S.A.Hoyng, N.Kawai, and K.D.Bloch (2008).
Bone morphogenetic protein (BMP) type II receptor is required for BMP-mediated growth arrest and differentiation in pulmonary artery smooth muscle cells.
  J Biol Chem, 283, 3877-3888.  
18768470 R.Stamler, H.T.Keutmann, Y.Sidis, C.Kattamuri, A.Schneyer, and T.B.Thompson (2008).
  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.  
18397882 Y.Makanji, K.L.Walton, M.C.Wilce, K.L.Chan, D.M.Robertson, and C.A.Harrison (2008).
Suppression of inhibin A biological activity by alterations in the binding site for betaglycan.
  J Biol Chem, 283, 16743-16751.  
17258738 B.H.Jung, S.E.Beck, J.Cabral, E.Chau, B.L.Cabrera, A.Fiorino, E.J.Smith, M.Bocanegra, and J.M.Carethers (2007).
Activin type 2 receptor restoration in MSI-H colon cancer suppresses growth and enhances migration with activin.
  Gastroenterology, 132, 633-644.  
17661740 B.Robert (2007).
Bone morphogenetic protein signaling in limb outgrowth and patterning.
  Dev Growth Differ, 49, 455-468.  
18000526 B.Schmierer, and C.S.Hill (2007).
TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility.
  Nat Rev Mol Cell Biol, 8, 970-982.  
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
17924340 J.D.Karkera, J.S.Lee, E.Roessler, S.Banerjee-Basu, M.V.Ouspenskaia, J.Mez, E.Goldmuntz, P.Bowers, J.Towbin, J.W.Belmont, A.D.Baxevanis, A.F.Schier, and M.Muenke (2007).
Loss-of-function mutations in growth differentiation factor-1 (GDF1) are associated with congenital heart defects in humans.
  Am J Hum Genet, 81, 987-994.  
17643432 P.T.Loverde, A.Osman, and A.Hinck (2007).
Schistosoma mansoni: TGF-beta signaling pathways.
  Exp Parasitol, 117, 304-317.  
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
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.  
16864795 D.M.Umulis, M.Serpe, M.B.O'Connor, and H.G.Othmer (2006).
Robust, bistable patterning of the dorsal surface of the Drosophila embryo.
  Proc Natl Acad Sci U S A, 103, 11613-11618.  
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
16831902 V.Rosen (2006).
BMP and BMP inhibitors in bone.
  Ann N Y Acad Sci, 1068, 19-25.  
16765900 X.Wang, R.H.Baloh, J.Milbrandt, and K.C.Garcia (2006).
Structure of artemin complexed with its receptor GFRalpha3: convergent recognition of glial cell line-derived neurotrophic factors.
  Structure, 14, 1083-1092.
PDB codes: 2gh0 2gyr 2gyz
15734148 C.A.Harrison, P.C.Gray, W.W.Vale, and D.M.Robertson (2005).
Antagonists of activin signaling: mechanisms and potential biological applications.
  Trends Endocrinol Metab, 16, 73-78.  
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.  
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.  
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
15883158 P.B.Yu, H.Beppu, N.Kawai, E.Li, and K.D.Bloch (2005).
Bone morphogenetic protein (BMP) type II receptor deletion reveals BMP ligand-specific gain of signaling in pulmonary artery smooth muscle cells.
  J Biol Chem, 280, 24443-24450.  
15977175 R.C.Albertson, T.L.Payne-Ferreira, J.Postlethwait, and P.C.Yelick (2005).
Zebrafish acvr2a and acvr2b exhibit distinct roles in craniofacial development.
  Dev Dyn, 233, 1405-1418.  
15549676 R.L.Rich, and D.G.Myszka (2005).
Survey of the year 2003 commercial optical biosensor literature.
  J Mol Recognit, 18, 1.  
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.  
15475360 E.del Re, Y.Sidis, D.A.Fabrizio, H.Y.Lin, and A.Schneyer (2004).
Reconstitution and analysis of soluble inhibin and activin receptor complexes in a cell-free system.
  J Biol Chem, 279, 53126-53135.  
14730303 G.Lahav, N.Rosenfeld, A.Sigal, N.Geva-Zatorsky, A.J.Levine, M.B.Elowitz, and U.Alon (2004).
Dynamics of the p53-Mdm2 feedback loop in individual cells.
  Nat Genet, 36, 147-150.  
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.  
14746809 Caestecker (2004).
The transforming growth factor-beta superfamily of receptors.
  Cytokine Growth Factor Rev, 15, 1.  
14966532 S.K.Cheng, F.Olale, A.H.Brivanlou, and A.F.Schier (2004).
Lefty blocks a subset of TGFbeta signals by antagonizing EGF-CFC coreceptors.
  PLoS Biol, 2, E30.  
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
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.  
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.  
12682303 P.C.Gray, C.A.Harrison, and W.Vale (2003).
Cripto forms a complex with activin and type II activin receptors and can block activin signaling.
  Proc Natl Acad Sci U S A, 100, 5193-5198.  
14559178 W.Sebald, and T.D.Mueller (2003).
The interaction of BMP-7 and ActRII implicates a new mode of receptor assembly.
  Trends Biochem Sci, 28, 518-521.  
12809600 Y.Shi, and J.Massagué (2003).
Mechanisms of TGF-beta signaling from cell membrane to the nucleus.
  Cell, 113, 685-700.  
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.