6ov7

From Proteopedia

(Difference between revisions)

Current revision

CFTR Associated Ligand (CAL) PDZ domain bound to peptide kCAL01

Structural highlights

6ov7 is a 4 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.71Å
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

The CFTR-associated ligand PDZ domain (CALP) binds to the cystic fibrosis transmembrane conductance regulator (CFTR) and mediates lysosomal degradation of mature CFTR. Inhibition of this interaction has been explored as a therapeutic avenue for cystic fibrosis. Previously, we reported the ensemble-based computational design of a novel peptide inhibitor of CALP, which resulted in the most binding-efficient inhibitor to date. This inhibitor, kCAL01, was designed using OSPREY and evinced significant biological activity in in vitro cell-based assays. Here, we report a crystal structure of kCAL01 bound to CALP and compare structural features against iCAL36, a previously developed inhibitor of CALP. We compute side-chain energy landscapes for each structure to not only enable approximation of binding thermodynamics, but also reveal ensemble features that contribute to the comparatively efficient binding of kCAL01. Finally, we compare the previously reported design ensemble for kCAL01 vs. the new crystal structure and show that, despite small differences between the design model and crystal structure, significant biophysical features that enhance inhibitor binding are captured in the design ensemble. This suggests not only that ensemble-based design captured thermodynamically significant features observed in vitro, but also that a design eschewing ensembles would miss the kCAL01 sequence entirely.

Computational Analysis of Energy Landscapes Reveals Dynamic Features that Contribute to Binding of Inhibitors to CFTR-Associated Ligand.,Holt GT, Jou JD, Gill NP, Lowegard AU, Martin JW, Madden DR, Donald BR J Phys Chem B. 2019 Nov 7. doi: 10.1021/acs.jpcb.9b07278. PMID:31697075^[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
↑ Holt GT, Jou JD, Gill NP, Lowegard AU, Martin JW, Madden DR, Donald BR. Computational Analysis of Energy Landscapes Reveals Dynamic Features that Contribute to Binding of Inhibitors to CFTR-Associated Ligand. J Phys Chem B. 2019 Nov 7. doi: 10.1021/acs.jpcb.9b07278. PMID:31697075 doi:http://dx.doi.org/10.1021/acs.jpcb.9b07278

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/6ov7"

Categories: Homo sapiens | Large Structures | Synthetic construct | Gill NP | Madden DR

@@ Line 3: / Line 3: @@
 <StructureSection load='6ov7' size='340' side='right'caption='[[6ov7]], [[Resolution|resolution]] 1.71&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6ov7]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6OV7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6OV7 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6ov7]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6OV7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6OV7 FirstGlance]. <br>
-</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GOPC, CAL, FIG ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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]] 1.71&#8491;</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=6ov7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ov7 OCA], [http://pdbe.org/6ov7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ov7 RCSB], [http://www.ebi.ac.uk/pdbsum/6ov7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ov7 ProSAT]</span></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=6ov7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ov7 OCA], [https://pdbe.org/6ov7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ov7 RCSB], [https://www.ebi.ac.uk/pdbsum/6ov7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ov7 ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://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>
+[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 ==
-[[http://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>
+[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 ==
@@ Line 24: / Line 24: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Gill, N P]]
+[[Category: Synthetic construct]]
-[[Category: Madden, D R]]
+[[Category: Gill NP]]
-[[Category: Complex]]
+[[Category: Madden DR]]
-[[Category: Inhibitor]]
-[[Category: Pdz domain]]
-[[Category: Peptide binding protein]]

6ov7

From Proteopedia

Current revision

CFTR Associated Ligand (CAL) PDZ domain bound to peptide kCAL01

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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