6ocx

From Proteopedia

(Difference between revisions)

Current revision

Structure of human CIB1 in complex with peptide inhibitor UNC10245109

Structural highlights

6ocx is a 8 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 1.9Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CIB1_HUMAN May convert the inactive conformation of integrin alpha-IIb/beta3 to an active form through binding to the integrin cytoplasmic domain. Induces cell migration and spreading mediated through integrin (possibly via focal adhesion complexes). Functions as a negative regulator of stress activated MAP kinase (MAPK) signaling pathways. May play a role in regulation of apoptosis. Interacts with and up-regulates PTK2/FAK1 activity. Down regulates inositol 1,4,5-trisphosphate receptor-dependent calcium signaling. Participates in endomitotic cell cycle, a form of mitosis in which both karyokinesis and cytokinesis are interrupted and is a hallmark of megakaryocyte differentiation.^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

Calcium and integrin binding protein 1 (CIB1) is an EF-hand-containing, small intracellular protein that has recently been implicated in cancer cell survival and proliferation. In particular, CIB1 depletion significantly impairs tumor growth in triple-negative breast cancer (TNBC). Thus, CIB1 is a potentially attractive target for cancer chemotherapy that has yet to be validated by a chemical probe. To produce a probe molecule to the CIB1 helix 10 (H10) pocket and demonstrate that it is a viable target for molecular intervention, we employed random peptide phage display to screen and select CIB1-binding peptides. The top peptide sequence selected, UNC10245092, was produced synthetically, and binding to CIB1 was confirmed by isothermal titration calorimetry (ITC) and a time-resolved fluorescence resonance energy transfer (TR-FRET) assay. Both assays showed that the peptide bound to CIB1 with low nanomolar affinity. CIB1 was cocrystallized with UNC10245092, and the 2.1 A resolution structure revealed that the peptide binds as an alpha-helix in the H10 pocket, displacing the CIB1 C-terminal H10 helix and causing conformational changes in H7 and H8. UNC10245092 was further derivatized with a C-terminal Tat-derived cell penetrating peptide (CPP) to demonstrate its effects on TNBC cells in culture, which are consistent with results of CIB1 depletion. These studies provide a first-in-class chemical tool for CIB1 inhibition in cell culture and validate the CIB1 H10 pocket for future probe and drug discovery efforts.

Discovery and Characterization of Peptide Inhibitors for Calcium and Integrin Binding Protein 1.,Puhl AC, Bogart JW, Haberman VA, Larson JE, Godoy AS, Norris-Drouin JL, Cholensky SH, Leisner TM, Frye SV, Parise LV, Bowers AA, Pearce KH ACS Chem Biol. 2020 Jun 19;15(6):1505-1516. doi: 10.1021/acschembio.0c00144. Epub, 2020 May 26. PMID:32383857^[7]

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

References

↑ Naik UP, Naik MU. Association of CIB with GPIIb/IIIa during outside-in signaling is required for platelet spreading on fibrinogen. Blood. 2003 Aug 15;102(4):1355-62. Epub 2003 Apr 24. PMID:12714504 doi:10.1182/blood-2003-02-0591
↑ Naik MU, Naik UP. Calcium-and integrin-binding protein regulates focal adhesion kinase activity during platelet spreading on immobilized fibrinogen. Blood. 2003 Nov 15;102(10):3629-36. Epub 2003 Jul 24. PMID:12881299 doi:10.1182/blood-2003-05-1703
↑ Tahara E Jr, Tahara H, Kanno M, Naka K, Takeda Y, Matsuzaki T, Yamazaki R, Ishihara H, Yasui W, Barrett JC, Ide T, Tahara E. G1P3, an interferon inducible gene 6-16, is expressed in gastric cancers and inhibits mitochondrial-mediated apoptosis in gastric cancer cell line TMK-1 cell. Cancer Immunol Immunother. 2005 Aug;54(8):729-40. Epub 2005 Feb 1. PMID:15685448 doi:10.1007/s00262-004-0645-2
↑ Hennigs JK, Burhenne N, Stahler F, Winnig M, Walter B, Meyerhof W, Schmale H. Sweet taste receptor interacting protein CIB1 is a general inhibitor of InsP3-dependent Ca2+ release in vivo. J Neurochem. 2008 Sep;106(5):2249-62. doi: 10.1111/j.1471-4159.2008.05563.x. PMID:18627437 doi:10.1111/j.1471-4159.2008.05563.x
↑ Yoon KW, Cho JH, Lee JK, Kang YH, Chae JS, Kim YM, Kim J, Kim EK, Kim SE, Baik JH, Naik UP, Cho SG, Choi EJ. CIB1 functions as a Ca(2+)-sensitive modulator of stress-induced signaling by targeting ASK1. Proc Natl Acad Sci U S A. 2009 Oct 13;106(41):17389-94. doi:, 10.1073/pnas.0812259106. Epub 2009 Sep 29. PMID:19805025 doi:10.1073/pnas.0812259106
↑ Kostyak JC, Naik UP. Calcium- and integrin-binding protein 1 regulates endomitosis and its interaction with Polo-like kinase 3 is enhanced in endomitotic Dami cells. PLoS One. 2011 Jan 14;6(1):e14513. doi: 10.1371/journal.pone.0014513. PMID:21264284 doi:10.1371/journal.pone.0014513
↑ Puhl AC, Bogart JW, Haberman VA, Larson JE, Godoy AS, Norris-Drouin JL, Cholensky SH, Leisner TM, Frye SV, Parise LV, Bowers AA, Pearce KH. Discovery and Characterization of Peptide Inhibitors for Calcium and Integrin Binding Protein 1. ACS Chem Biol. 2020 Jun 19;15(6):1505-1516. doi: 10.1021/acschembio.0c00144. Epub, 2020 May 26. PMID:32383857 doi:http://dx.doi.org/10.1021/acschembio.0c00144

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6ocx"

Categories: Homo sapiens | Large Structures | Godoy AS | Pearce K | Puhl AC

@@ Line 3: / Line 3: @@
 <StructureSection load='6ocx' size='340' side='right'caption='[[6ocx]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6ocx]] is a 8 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=6OCX OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6OCX FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6ocx]] is a 8 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=6OCX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6OCX FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</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]] 1.9&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CIB1, CIB, KIP, PRKDCIP ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6ocx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ocx OCA], [http://pdbe.org/6ocx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ocx RCSB], [http://www.ebi.ac.uk/pdbsum/6ocx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ocx 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=6ocx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ocx OCA], [https://pdbe.org/6ocx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ocx RCSB], [https://www.ebi.ac.uk/pdbsum/6ocx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ocx ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/CIB1_HUMAN CIB1_HUMAN]] May convert the inactive conformation of integrin alpha-IIb/beta3 to an active form through binding to the integrin cytoplasmic domain. Induces cell migration and spreading mediated through integrin (possibly via focal adhesion complexes). Functions as a negative regulator of stress activated MAP kinase (MAPK) signaling pathways. May play a role in regulation of apoptosis. Interacts with and up-regulates PTK2/FAK1 activity. Down regulates inositol 1,4,5-trisphosphate receptor-dependent calcium signaling. Participates in endomitotic cell cycle, a form of mitosis in which both karyokinesis and cytokinesis are interrupted and is a hallmark of megakaryocyte differentiation.<ref>PMID:12714504</ref> <ref>PMID:12881299</ref> <ref>PMID:15685448</ref> <ref>PMID:18627437</ref> <ref>PMID:19805025</ref> <ref>PMID:21264284</ref>
+[https://www.uniprot.org/uniprot/CIB1_HUMAN CIB1_HUMAN] May convert the inactive conformation of integrin alpha-IIb/beta3 to an active form through binding to the integrin cytoplasmic domain. Induces cell migration and spreading mediated through integrin (possibly via focal adhesion complexes). Functions as a negative regulator of stress activated MAP kinase (MAPK) signaling pathways. May play a role in regulation of apoptosis. Interacts with and up-regulates PTK2/FAK1 activity. Down regulates inositol 1,4,5-trisphosphate receptor-dependent calcium signaling. Participates in endomitotic cell cycle, a form of mitosis in which both karyokinesis and cytokinesis are interrupted and is a hallmark of megakaryocyte differentiation.<ref>PMID:12714504</ref> <ref>PMID:12881299</ref> <ref>PMID:15685448</ref> <ref>PMID:18627437</ref> <ref>PMID:19805025</ref> <ref>PMID:21264284</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 23: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Godoy, A S]]
+[[Category: Godoy AS]]
-[[Category: Pearce, K]]
+[[Category: Pearce K]]
-[[Category: Puhl, A C]]
+[[Category: Puhl AC]]
-[[Category: Cancer]]
-[[Category: Cib1]]
-[[Category: Metal binding protein]]

6ocx

From Proteopedia

Current revision

Structure of human CIB1 in complex with peptide inhibitor UNC10245109

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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