3nh7: Difference between revisions
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==Crystal structure of the neutralizing Fab fragment AbD1556 bound to the BMP type I receptor IA== | |||
<StructureSection load='3nh7' size='340' side='right'caption='[[3nh7]], [[Resolution|resolution]] 2.70Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3nh7]] is a 12 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3NH7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3NH7 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7Å</td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3nh7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3nh7 OCA], [https://pdbe.org/3nh7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3nh7 RCSB], [https://www.ebi.ac.uk/pdbsum/3nh7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3nh7 ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://www.uniprot.org/uniprot/BMR1A_HUMAN BMR1A_HUMAN] Defects in BMPR1A are a cause of juvenile polyposis syndrome (JPS) [MIM:[https://omim.org/entry/174900 174900]; also known as juvenile intestinal polyposis (JIP). JPS is an autosomal dominant gastrointestinal hamartomatous polyposis syndrome in which patients are at risk for developing gastrointestinal cancers. The lesions are typified by a smooth histological appearance, predominant stroma, cystic spaces and lack of a smooth muscle core. Multiple juvenile polyps usually occur in a number of Mendelian disorders. Sometimes, these polyps occur without associated features as in JPS; here, polyps tend to occur in the large bowel and are associated with an increased risk of colon and other gastrointestinal cancers.<ref>PMID:11381269</ref> <ref>PMID:11536076</ref> <ref>PMID:12417513</ref> <ref>PMID:12136244</ref> <ref>PMID:12630959</ref> Defects in BMPR1A are a cause of Cowden disease (CD) [MIM:[https://omim.org/entry/158350 158350]. CD is an autosomal dominant cancer syndrome characterized by multiple hamartomas and by a high risk for breast, thyroid and endometrial cancers.<ref>PMID:11381269</ref> <ref>PMID:11536076</ref> Defects in BMPR1A are the cause of hereditary mixed polyposis syndrome 2 (HMPS2) [MIM:[https://omim.org/entry/610069 610069]. Hereditary mixed polyposis syndrome (HMPS) is characterized by atypical juvenile polyps, colonic adenomas, and colorectal carcinomas.<ref>PMID:11381269</ref> Note=A microdeletion of chromosome 10q23 involving BMPR1A and PTEN is a cause of chromosome 10q23 deletion syndrome, which shows overlapping features of the following three disorders: Bannayan-Zonana syndrome, Cowden disease and juvenile polyposis syndrome.<ref>PMID:11381269</ref> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/BMR1A_HUMAN BMR1A_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. Receptor for BMP-2 and BMP-4. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
BACKGROUND: Members of the TGF-beta superfamily are characterized by a highly promiscuous ligand-receptor interaction as is readily apparent from the numeral discrepancy of only seven type I and five type II receptors available for more than 40 ligands. Structural and functional studies have been used to address the question of how specific signals can be deduced from a limited number of receptor combinations and to unravel the molecular mechanisms underlying the protein-protein recognition that allow such limited specificity. PRINCIPAL FINDINGS: In this study we have investigated how an antigen binding antibody fragment (Fab) raised against the extracellular domain of the BMP receptor type IA (BMPR-IA) recognizes the receptor's BMP-2 binding epitope and thereby neutralizes BMP-2 receptor activation. The crystal structure of the complex of the BMPR-IA ectodomain bound to the Fab AbD1556 revealed that the contact surface of BMPR-IA overlaps extensively with the contact surface for BMP-2 interaction. Although the structural epitopes of BMPR-IA to both binding partners coincides, the structures of BMPR-IA in the two complexes differ significantly. In contrast to the structural differences, alanine-scanning mutagenesis of BMPR-IA showed that the functional determinants for binding to the antibody and BMP-2 are almost identical. CONCLUSIONS: Comparing the structures of BMPR-IA bound to BMP-2 or bound to the Fab AbD1556 with the structure of unbound BMPR-IA shows that binding of BMPR-IA to its interaction partners follows a selection fit mechanism, possibly indicating that the ligand promiscuity of BMPR-IA is inherently encoded by structural adaptability. The functional and structural analysis of the BMPR-IA binding antibody AbD1556 mimicking the BMP-2 binding epitope may thus pave the way for the design of low-molecular weight synthetic receptor binders/inhibitors. | |||
A selection fit mechanism in BMP receptor IA as a possible source for BMP ligand-receptor promiscuity.,Harth S, Kotzsch A, Hu J, Sebald W, Mueller TD PLoS One. 2010 Sep 28;5(9). pii: e13049. PMID:20927405<ref>PMID:20927405</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3nh7" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[Antibody|Antibody]] | *[[Antibody 3D structures|Antibody 3D structures]] | ||
*[[3D structures of human antibody|3D structures of human antibody]] | |||
== | == References == | ||
< | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Harth | [[Category: Harth S]] | ||
[[Category: Mueller | [[Category: Mueller TD]] | ||
[[Category: Sebald | [[Category: Sebald W]] | ||