View source for 4nmp


==CFTR Associated Ligand (CAL) PDZ domain bound to peptide iCAL36(Ac-K-3) (ANSRWP[Ac-K]SII)==
<StructureSection load='4nmp' size='340' side='right'caption='[[4nmp]], [[Resolution|resolution]] 1.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4nmp]] is a 4 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=4NMP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4NMP 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]] 1.3&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ALY:N(6)-ACETYLLYSINE'>ALY</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PRD_001196:iCAL36(Ac-K-3)+peptide'>PRD_001196</scene></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=4nmp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nmp OCA], [https://pdbe.org/4nmp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4nmp RCSB], [https://www.ebi.ac.uk/pdbsum/4nmp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4nmp ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/GOPC_HUMAN GOPC_HUMAN] Note=A chromosomal aberration involving GOPC is found in a glioblastoma multiforme sample. An intra-chromosomal deletion del(6)(q21q21) is responsible for the formation of GOPC-ROS1 chimeric protein which has a constitutive receptor tyrosine kinase activity.<ref>PMID:12661006</ref> 
== Function ==
[https://www.uniprot.org/uniprot/GOPC_HUMAN GOPC_HUMAN] Plays a role in intracellular protein trafficking and degradation. May regulate CFTR chloride currents and acid-induced ASIC3 currents by modulating cell surface expression of both channels. May also regulate the intracellular trafficking of the ADR1B receptor. May play a role in autophagy. Overexpression results in CFTR intracellular retention and degradation in the lysosomes.<ref>PMID:11707463</ref> <ref>PMID:14570915</ref> <ref>PMID:15358775</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
PDZ domains are protein-protein interaction modules that coordinate multiple signaling and trafficking pathways in the cell and that include active therapeutic targets for diseases such as cancer, cystic fibrosis, and addiction. Our previous work characterized a PDZ interaction that restricts the apical membrane half-life of the cystic fibrosis transmembrane conductance regulator (CFTR). Using iterative cycles of peptide-array and solution-binding analysis, we targeted the PDZ domain of the CFTR-Associated Ligand (CAL), and showed that an engineered peptide inhibitor rescues cell-surface expression of the most common CFTR disease mutation DeltaF508. Here, we present a series of scaffolds containing chemically modifiable side chains at all non-motif positions along the CAL PDZ domain binding cleft. Concordant equilibrium dissociation constants were determined in parallel by fluorescence polarization, isothermal titration calorimetry, and surface plasmon resonance techniques, confirming robust affinity for each scaffold and revealing an enthalpically driven mode of inhibitor binding. Structural studies demonstrate a conserved binding mode for each peptide, opening the possibility of combinatorial modification. Finally, we diversified one of our peptide scaffolds with halogenated substituents that yielded modest increases in binding affinity. Overall, this work validates our approach and provides a stereochemical foundation for further CAL inhibitor design and screening.

Chemically Modified Peptide Scaffolds Target the CFTR-Associated Ligand PDZ Domain.,Amacher JF, Zhao R, Spaller MR, Madden DR PLoS One. 2014 Aug 19;9(8):e103650. doi: 10.1371/journal.pone.0103650., eCollection 2014. PMID:25136860<ref>PMID:25136860</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4nmp" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Amacher JF]]
[[Category: Madden DR]]