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The | ==Human NBD1 of CFTR in complex with nanobodies D12 and T4== | ||
<StructureSection load='6gjs' size='340' side='right'caption='[[6gjs]], [[Resolution|resolution]] 1.95Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6gjs]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GJS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GJS FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ATP:ADENOSINE-5-TRIPHOSPHATE'>ATP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Channel-conductance-controlling_ATPase Channel-conductance-controlling ATPase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.6.3.49 3.6.3.49] </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=6gjs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6gjs OCA], [http://pdbe.org/6gjs PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6gjs RCSB], [http://www.ebi.ac.uk/pdbsum/6gjs PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6gjs ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/Q20BJ8_HUMAN Q20BJ8_HUMAN]] Epithelial ion channel that plays an important role in the regulation of epithelial ion and water transport and fluid homeostasis. Mediates the transport of chloride ions across the cell membrane. Channel activity is coupled to ATP hydrolysis. The ion channel is also permeable to HCO(3-); selectivity depends on the extracellular chloride concentration. Exerts its function also by modulating the activity of other ion channels and transporters. Contributes to the regulation of the pH and the ion content of the epithelial fluid layer.[RuleBase:RU362037] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The leading cause of cystic fibrosis (CF) is the deletion of phenylalanine 508 (F508del) in the first nucleotide-binding domain (NBD1) of the cystic fibrosis transmembrane conductance regulator (CFTR). The mutation affects the thermodynamic stability of the domain and the integrity of the interface between NBD1 and the transmembrane domain leading to its clearance by the quality control system. Here, we develop nanobodies targeting NBD1 of human CFTR and demonstrate their ability to stabilize both isolated NBD1 and full-length protein. Crystal structures of NBD1-nanobody complexes provide an atomic description of the epitopes and reveal the molecular basis for stabilization. Furthermore, our data uncover a conformation of CFTR, involving detachment of NBD1 from the transmembrane domain, which contrast with the compact assembly observed in cryo-EM structures. This unexpected interface rearrangement is likely to have major relevance for CF pathogenesis but also for the normal function of CFTR and other ABC proteins. | |||
Domain-interface dynamics of CFTR revealed by stabilizing nanobodies.,Sigoillot M, Overtus M, Grodecka M, Scholl D, Garcia-Pino A, Laeremans T, He L, Pardon E, Hildebrandt E, Urbatsch I, Steyaert J, Riordan JR, Govaerts C Nat Commun. 2019 Jun 14;10(1):2636. doi: 10.1038/s41467-019-10714-y. PMID:31201318<ref>PMID:31201318</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6gjs" style="background-color:#fffaf0;"></div> | ||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Channel-conductance-controlling ATPase]] | |||
[[Category: Large Structures]] | |||
[[Category: Garcia-Pino, A]] | [[Category: Garcia-Pino, A]] | ||
[[Category: Govaerts, C]] | [[Category: Govaerts, C]] | ||
[[Category: Grodecka, M]] | [[Category: Grodecka, M]] | ||
[[Category: He, L]] | [[Category: He, L]] | ||
[[Category: Hildebrandt, E]] | [[Category: Hildebrandt, E]] | ||
[[Category: Laeremans, T]] | |||
[[Category: Overtus, M]] | |||
[[Category: Pardon, E]] | |||
[[Category: Riordan, J R]] | |||
[[Category: Scholl, D]] | [[Category: Scholl, D]] | ||
[[Category: Sigoillot, M]] | |||
[[Category: Steyaert, J]] | |||
[[Category: Urbatsch, I]] | |||
[[Category: Cftr]] | |||
[[Category: Conformational dynamic]] | |||
[[Category: Cystic fibrosis]] | |||
[[Category: Immune system]] | |||
[[Category: Nanobody]] | |||
[[Category: Thermal stabilization]] | |||
Latest revision as of 09:46, 26 June 2019
Human NBD1 of CFTR in complex with nanobodies D12 and T4Human NBD1 of CFTR in complex with nanobodies D12 and T4
Structural highlights
Function[Q20BJ8_HUMAN] Epithelial ion channel that plays an important role in the regulation of epithelial ion and water transport and fluid homeostasis. Mediates the transport of chloride ions across the cell membrane. Channel activity is coupled to ATP hydrolysis. The ion channel is also permeable to HCO(3-); selectivity depends on the extracellular chloride concentration. Exerts its function also by modulating the activity of other ion channels and transporters. Contributes to the regulation of the pH and the ion content of the epithelial fluid layer.[RuleBase:RU362037] Publication Abstract from PubMedThe leading cause of cystic fibrosis (CF) is the deletion of phenylalanine 508 (F508del) in the first nucleotide-binding domain (NBD1) of the cystic fibrosis transmembrane conductance regulator (CFTR). The mutation affects the thermodynamic stability of the domain and the integrity of the interface between NBD1 and the transmembrane domain leading to its clearance by the quality control system. Here, we develop nanobodies targeting NBD1 of human CFTR and demonstrate their ability to stabilize both isolated NBD1 and full-length protein. Crystal structures of NBD1-nanobody complexes provide an atomic description of the epitopes and reveal the molecular basis for stabilization. Furthermore, our data uncover a conformation of CFTR, involving detachment of NBD1 from the transmembrane domain, which contrast with the compact assembly observed in cryo-EM structures. This unexpected interface rearrangement is likely to have major relevance for CF pathogenesis but also for the normal function of CFTR and other ABC proteins. Domain-interface dynamics of CFTR revealed by stabilizing nanobodies.,Sigoillot M, Overtus M, Grodecka M, Scholl D, Garcia-Pino A, Laeremans T, He L, Pardon E, Hildebrandt E, Urbatsch I, Steyaert J, Riordan JR, Govaerts C Nat Commun. 2019 Jun 14;10(1):2636. doi: 10.1038/s41467-019-10714-y. PMID:31201318[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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