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2hlq

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Revision as of 06:22, 27 June 2018

Crystal Structure of the Extracellular Domain of the Type II BMP Receptor

Structural highlights

2hlq is a 1 chain structure with sequence from Ovis ammon aries. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Gene:	BMPRII (Ovis ammon aries)
Activity:	Receptor protein serine/threonine kinase, with EC number 2.7.11.30
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[BMPR2_HUMAN] Defects in BMPR2 are the cause of primary pulmonary hypertension (PPH1) [MIM:178600]. PPH1 is a rare autosomal dominant disorder characterized by plexiform lesions of proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a mean age at onset of 36 years. Penetrance is reduced. Although familial PPH1 is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] Defects in BMPR2 are a cause of pulmonary venoocclusive disease (PVOD) [MIM:265450]. PVOD is a rare form of pulmonary hypertension in which the vascular changes originate in the small pulmonary veins and venules. The pathogenesis is unknown and any link with PPH1 has been speculative. The finding of PVOD associated with a BMPR2 mutation reveals a possible pathogenetic connection with PPH1.^[7] ^[8]

Function

[BMPR2_HUMAN] On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Binds to BMP-7, BMP-2 and, less efficiently, BMP-4. Binding is weak but enhanced by the presence of type I receptors for BMPs.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

BMPRII is a type II TGF-beta serine threonine kinase receptor which is integral to the bone morphogenetic protein (BMP) signalling pathway. It is known to bind BMP and growth differentiation factor (GDF) ligands, and has overlapping ligand specificity with the activin type II receptor, ActRII. In contrast to activin and TGF-beta type ligands, BMPs bind to type II receptors with lower affinity than type I receptors. Crystals of the BMPRII ectodomain were grown in two different forms, both of which diffracted to high resolution. The tetragonal form exhibited some disorder, whereas the entire polypeptide was seen in the orthorhombic form. The two structures retain the basic three-finger toxin fold of other TGF-beta receptor ectodomains, and share the main hydrophobic patch used by ActRII to bind various ligands. However, they present different conformations of the A-loop at the periphery of the proposed ligand-binding interface, in conjunction with rearrangement of a disulfide bridge within the loop. This particular disulfide (Cys94-Cys117) is only present in BMPRII and activin receptors, suggesting that it is important for their likely shared mode of binding. Evidence is presented that the two crystal forms represent ligand-bound and free conformations of BMPRII. Comparison with the solved structure of ActRII bound to BMP2 suggests that His87, unique amongst TGF-beta receptors, may play a key role in ligand recognition.

High resolution structures of the bone morphogenetic protein type II receptor in two crystal forms: implications for ligand binding.,Mace PD, Cutfield JF, Cutfield SM Biochem Biophys Res Commun. 2006 Dec 29;351(4):831-8. Epub 2006 Nov 10. PMID:17094948^[9]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Deng Z, Morse JH, Slager SL, Cuervo N, Moore KJ, Venetos G, Kalachikov S, Cayanis E, Fischer SG, Barst RJ, Hodge SE, Knowles JA. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet. 2000 Sep;67(3):737-44. Epub 2000 Jul 20. PMID:10903931 doi:10.1086/303059
↑ Thomson JR, Machado RD, Pauciulo MW, Morgan NV, Humbert M, Elliott GC, Ward K, Yacoub M, Mikhail G, Rogers P, Newman J, Wheeler L, Higenbottam T, Gibbs JS, Egan J, Crozier A, Peacock A, Allcock R, Corris P, Loyd JE, Trembath RC, Nichols WC. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet. 2000 Oct;37(10):741-5. PMID:11015450
↑ Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA 3rd, Loyd JE, Nichols WC, Trembath RC. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nat Genet. 2000 Sep;26(1):81-4. PMID:10973254 doi:10.1038/79226
↑ Machado RD, Pauciulo MW, Thomson JR, Lane KB, Morgan NV, Wheeler L, Phillips JA 3rd, Newman J, Williams D, Galie N, Manes A, McNeil K, Yacoub M, Mikhail G, Rogers P, Corris P, Humbert M, Donnai D, Martensson G, Tranebjaerg L, Loyd JE, Trembath RC, Nichols WC. BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Am J Hum Genet. 2001 Jan;68(1):92-102. Epub 2000 Dec 12. PMID:11115378
↑ Humbert M, Deng Z, Simonneau G, Barst RJ, Sitbon O, Wolf M, Cuervo N, Moore KJ, Hodge SE, Knowles JA, Morse JH. BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives. Eur Respir J. 2002 Sep;20(3):518-23. PMID:12358323
↑ Sankelo M, Flanagan JA, Machado R, Harrison R, Rudarakanchana N, Morrell N, Dixon M, Halme M, Puolijoki H, Kere J, Elomaa O, Kupari M, Raisanen-Sokolowski A, Trembath RC, Laitinen T. BMPR2 mutations have short lifetime expectancy in primary pulmonary hypertension. Hum Mutat. 2005 Aug;26(2):119-24. PMID:15965979 doi:10.1002/humu.20200
↑ Runo JR, Vnencak-Jones CL, Prince M, Loyd JE, Wheeler L, Robbins IM, Lane KB, Newman JH, Johnson J, Nichols WC, Phillips JA 3rd. Pulmonary veno-occlusive disease caused by an inherited mutation in bone morphogenetic protein receptor II. Am J Respir Crit Care Med. 2003 Mar 15;167(6):889-94. Epub 2002 Nov 21. PMID:12446270 doi:10.1164/rccm.200208-861OC
↑ Machado RD, Aldred MA, James V, Harrison RE, Patel B, Schwalbe EC, Gruenig E, Janssen B, Koehler R, Seeger W, Eickelberg O, Olschewski H, Elliott CG, Glissmeyer E, Carlquist J, Kim M, Torbicki A, Fijalkowska A, Szewczyk G, Parma J, Abramowicz MJ, Galie N, Morisaki H, Kyotani S, Nakanishi N, Morisaki T, Humbert M, Simonneau G, Sitbon O, Soubrier F, Coulet F, Morrell NW, Trembath RC. Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat. 2006 Feb;27(2):121-32. PMID:16429395 doi:10.1002/humu.20285
↑ Mace PD, Cutfield JF, Cutfield SM. High resolution structures of the bone morphogenetic protein type II receptor in two crystal forms: implications for ligand binding. Biochem Biophys Res Commun. 2006 Dec 29;351(4):831-8. Epub 2006 Nov 10. PMID:17094948 doi:http://dx.doi.org/10.1016/j.bbrc.2006.10.109

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2hlq"

@@ Line 1: / Line 1: @@
 ==Crystal Structure of the Extracellular Domain of the Type II BMP Receptor==
 <StructureSection load='2hlq' size='340' side='right' caption='[[2hlq]], [[Resolution|resolution]] 1.45&Aring;' scene=''>
@@ Line 5: / Line 6: @@
 </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BMPRII ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9940 Ovis ammon aries])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein_serine/threonine_kinase Receptor protein serine/threonine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.30 2.7.11.30] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2hlq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2hlq OCA], [http://pdbe.org/2hlq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2hlq RCSB], [http://www.ebi.ac.uk/pdbsum/2hlq PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2hlq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2hlq OCA], [http://pdbe.org/2hlq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2hlq RCSB], [http://www.ebi.ac.uk/pdbsum/2hlq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2hlq ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 15: / Line 16: @@
 Check<jmol>
   <jmolCheckbox>
-    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/hl/2hlq_consurf.spt"</scriptWhenChecked>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/hl/2hlq_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>

2hlq

From Proteopedia

Revision as of 06:22, 27 June 2018

Crystal Structure of the Extracellular Domain of the Type II BMP Receptor

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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