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4nmt

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CFTR Associated Ligand (CAL) PDZ domain bound to peptide iCAL36(TFA-K-1) (ANSRWPTS[Tfa-acyl-K]I)

Structural highlights

4nmt is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.4Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

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.^[1]

Function

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.^[2] ^[3] ^[4]

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^[5]

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

References

↑ Charest A, Lane K, McMahon K, Park J, Preisinger E, Conroy H, Housman D. Fusion of FIG to the receptor tyrosine kinase ROS in a glioblastoma with an interstitial del(6)(q21q21). Genes Chromosomes Cancer. 2003 May;37(1):58-71. PMID:12661006 doi:10.1002/gcc.10207
↑ Cheng J, Moyer BD, Milewski M, Loffing J, Ikeda M, Mickle JE, Cutting GR, Li M, Stanton BA, Guggino WB. A Golgi-associated PDZ domain protein modulates cystic fibrosis transmembrane regulator plasma membrane expression. J Biol Chem. 2002 Feb 1;277(5):3520-9. Epub 2001 Nov 13. PMID:11707463 doi:10.1074/jbc.M110177200
↑ Cheng J, Wang H, Guggino WB. Modulation of mature cystic fibrosis transmembrane regulator protein by the PDZ domain protein CAL. J Biol Chem. 2004 Jan 16;279(3):1892-8. Epub 2003 Oct 21. PMID:14570915 doi:10.1074/jbc.M308640200
↑ He J, Bellini M, Xu J, Castleberry AM, Hall RA. Interaction with cystic fibrosis transmembrane conductance regulator-associated ligand (CAL) inhibits beta1-adrenergic receptor surface expression. J Biol Chem. 2004 Nov 26;279(48):50190-6. Epub 2004 Sep 9. PMID:15358775 doi:10.1074/jbc.M404876200
↑ Amacher JF, Zhao R, Spaller MR, Madden DR. Chemically Modified Peptide Scaffolds Target the CFTR-Associated Ligand PDZ Domain. PLoS One. 2014 Aug 19;9(8):e103650. doi: 10.1371/journal.pone.0103650., eCollection 2014. PMID:25136860 doi:http://dx.doi.org/10.1371/journal.pone.0103650

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4nmt"

Categories: Homo sapiens | Large Structures | Amacher JF | Madden DR

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4nmt]] 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=4NMT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4NMT FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FAK:N~6~-(TRIFLUOROACETYL)-L-LYSINE'>FAK</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.4&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FAK:N~6~-(TRIFLUOROACETYL)-L-LYSINE'>FAK</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=4nmt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nmt OCA], [https://pdbe.org/4nmt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4nmt RCSB], [https://www.ebi.ac.uk/pdbsum/4nmt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4nmt ProSAT]</span></td></tr>
 </table>

4nmt

From Proteopedia

Current revision

CFTR Associated Ligand (CAL) PDZ domain bound to peptide iCAL36(TFA-K-1) (ANSRWPTS[Tfa-acyl-K]I)

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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