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4tnb

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Crystal Structure of G Protein-Coupled Receptor Kinase 5 in Complex with Sangivamycin

Structural highlights

4tnb is a 1 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 2.113Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

GRK5_HUMAN Serine/threonine kinase that phosphorylates preferentially the activated forms of a variety of G-protein-coupled receptors (GPCRs). Such receptor phosphorylation initiates beta-arrestin-mediated receptor desensitization, internalization, and signaling events leading to their down-regulation. Phosphorylates a variety of GPCRs, including adrenergic receptors, muscarinic acetylcholine receptors (more specifically Gi-coupled M2/M4 subtypes), dopamine receptors and opioid receptors. In addition to GPCRs, also phosphorylates various substrates: Hsc70-interacting protein/ST13, TP53/p53, HDAC5, and arrestin-1/ARRB1. Phosphorylation of ARRB1 by GRK5 inhibits G-protein independent MAPK1/MAPK3 signaling downstream of 5HT4-receptors. Phosphorylation of HDAC5, a repressor of myocyte enhancer factor 2 (MEF2) leading to nuclear export of HDAC5 and allowing MEF2-mediated transcription. Phosphorylation of TP53/p53, a crucial tumor suppressor, inhibits TP53/p53-mediated apoptosis. Phosphorylation of ST13 regulates internalization of the chemokine receptor. Phosphorylates rhodopsin (RHO) (in vitro) and a non G-protein-coupled receptor, LRP6 during Wnt signaling (in vitro).^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

G protein-coupled receptor kinases (GRKs) are members of the AGC kinase family and play a central role in mediating receptor phosphorylation and desensitization. One member of the family, GRK5, has been implicated in several human pathologies including heart failure, hypertension, cancer and Alzheimers disease. To gain mechanistic insight into GRK5 function, we determined a crystal structure of full-length human GRK5 at 1.8 angstrom resolution. GRK5 in complex with the ATP analog AMP-PNP or the nucleoside sangivamycin crystallized as a monomer. The C-terminal tail (C-tail) of AGC kinase domains is a highly conserved feature that is divided into 3 segments: the C-lobe tether (CLT), the active-site tether (AST), and the N-lobe tether (NLT). This domain is fully resolved in GRK5 and reveals novel interactions with nucleotide and N-lobe. Similar to other AGC kinases, the GRK5 AST is an integral part of the nucleotide-binding pocket, a feature not observed in other GRKs. The AST also mediates contact between the kinase N- and C-lobes facilitating closure of the kinase domain. The GRK5 NLT is largely displaced from its previously observed position in other GRKs. Moreover, the autophosphorylation sites in the NLT are capable of rapid cis-autophosphorylation suggesting high mobility of this region. In summary, we provide a snapshot of GRK5 in a partially closed state, where structural elements of the kinase domain C-tail are aligned to form novel interactions to nucleotide and N-lobe not previously observed in other GRKs. These findings should be important in the design of selective drugs that target GRK5.

Atomic Structure of G Protein-Coupled Receptor Kinase 5 (GRK5) Reveals Distinct Structural Features Novel for GRKs.,Komolov KE, Bhardwaj A, Benovic JL J Biol Chem. 2015 Jun 1. pii: jbc.M115.647297. PMID:26032409^[6]

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

References

↑ Barthet G, Carrat G, Cassier E, Barker B, Gaven F, Pillot M, Framery B, Pellissier LP, Augier J, Kang DS, Claeysen S, Reiter E, Baneres JL, Benovic JL, Marin P, Bockaert J, Dumuis A. Beta-arrestin1 phosphorylation by GRK5 regulates G protein-independent 5-HT4 receptor signalling. EMBO J. 2009 Sep 16;28(18):2706-18. Epub 2009 Aug 6. PMID:19661922 doi:http://dx.doi.org/emboj2009215
↑ Chen M, Philipp M, Wang J, Premont RT, Garrison TR, Caron MG, Lefkowitz RJ, Chen W. G Protein-coupled receptor kinases phosphorylate LRP6 in the Wnt pathway. J Biol Chem. 2009 Dec 11;284(50):35040-8. doi: 10.1074/jbc.M109.047456. Epub 2009, Oct 2. PMID:19801552 doi:10.1074/jbc.M109.047456
↑ Baameur F, Morgan DH, Yao H, Tran TM, Hammitt RA, Sabui S, McMurray JS, Lichtarge O, Clark RB. Role for the regulator of G-protein signaling homology domain of G protein-coupled receptor kinases 5 and 6 in beta 2-adrenergic receptor and rhodopsin phosphorylation. Mol Pharmacol. 2010 Mar;77(3):405-15. doi: 10.1124/mol.109.058115. Epub 2009 Dec , 28. PMID:20038610 doi:http://dx.doi.org/10.1124/mol.109.058115
↑ Chen X, Zhu H, Yuan M, Fu J, Zhou Y, Ma L. G-protein-coupled receptor kinase 5 phosphorylates p53 and inhibits DNA damage-induced apoptosis. J Biol Chem. 2010 Apr 23;285(17):12823-30. doi: 10.1074/jbc.M109.094243. Epub, 2010 Feb 2. PMID:20124405 doi:http://dx.doi.org/10.1074/jbc.M109.094243
↑ Barker BL, Benovic JL. G protein-coupled receptor kinase 5 phosphorylation of hip regulates internalization of the chemokine receptor CXCR4. Biochemistry. 2011 Aug 16;50(32):6933-41. doi: 10.1021/bi2005202. Epub 2011 Jul, 12. PMID:21728385 doi:http://dx.doi.org/10.1021/bi2005202
↑ Komolov KE, Bhardwaj A, Benovic JL. Atomic Structure of G Protein-Coupled Receptor Kinase 5 (GRK5) Reveals Distinct Structural Features Novel for GRKs. J Biol Chem. 2015 Jun 1. pii: jbc.M115.647297. PMID:26032409 doi:http://dx.doi.org/10.1074/jbc.M115.647297

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/4tnb"

Categories: Homo sapiens | Large Structures | Benovic JL | Bhardwaj A | Komolov KE

@@ Line 1: / Line 1: @@
 ==Crystal Structure of G Protein-Coupled Receptor Kinase 5 in Complex with Sangivamycin==
-<StructureSection load='4tnb' size='340' side='right' caption='[[4tnb]], [[Resolution|resolution]] 2.11&Aring;' scene=''>
+<StructureSection load='4tnb' size='340' side='right'caption='[[4tnb]], [[Resolution|resolution]] 2.11&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4tnb]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4TNB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4TNB FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4tnb]] is a 1 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=4TNB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4TNB FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SGV:SANGIVAMYCIN'>SGV</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]] 2.113&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4tnd|4tnd]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SGV:SANGIVAMYCIN'>SGV</scene></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/[G-protein-coupled_receptor]_kinase [G-protein-coupled receptor] kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.16 2.7.11.16] </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=4tnb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tnb OCA], [https://pdbe.org/4tnb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4tnb RCSB], [https://www.ebi.ac.uk/pdbsum/4tnb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4tnb ProSAT]</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=4tnb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tnb OCA], [http://pdbe.org/4tnb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4tnb RCSB], [http://www.ebi.ac.uk/pdbsum/4tnb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4tnb ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/GRK5_HUMAN GRK5_HUMAN]] Serine/threonine kinase that phosphorylates preferentially the activated forms of a variety of G-protein-coupled receptors (GPCRs). Such receptor phosphorylation initiates beta-arrestin-mediated receptor desensitization, internalization, and signaling events leading to their down-regulation. Phosphorylates a variety of GPCRs, including adrenergic receptors, muscarinic acetylcholine receptors (more specifically Gi-coupled M2/M4 subtypes), dopamine receptors and opioid receptors. In addition to GPCRs, also phosphorylates various substrates: Hsc70-interacting protein/ST13, TP53/p53, HDAC5, and arrestin-1/ARRB1. Phosphorylation of ARRB1 by GRK5 inhibits G-protein independent MAPK1/MAPK3 signaling downstream of 5HT4-receptors. Phosphorylation of HDAC5, a repressor of myocyte enhancer factor 2 (MEF2) leading to nuclear export of HDAC5 and allowing MEF2-mediated transcription. Phosphorylation of TP53/p53, a crucial tumor suppressor, inhibits TP53/p53-mediated apoptosis. Phosphorylation of ST13 regulates internalization of the chemokine receptor. Phosphorylates rhodopsin (RHO) (in vitro) and a non G-protein-coupled receptor, LRP6 during Wnt signaling (in vitro).<ref>PMID:19661922</ref> <ref>PMID:19801552</ref> <ref>PMID:20038610</ref> <ref>PMID:20124405</ref> <ref>PMID:21728385</ref>
+[https://www.uniprot.org/uniprot/GRK5_HUMAN GRK5_HUMAN] Serine/threonine kinase that phosphorylates preferentially the activated forms of a variety of G-protein-coupled receptors (GPCRs). Such receptor phosphorylation initiates beta-arrestin-mediated receptor desensitization, internalization, and signaling events leading to their down-regulation. Phosphorylates a variety of GPCRs, including adrenergic receptors, muscarinic acetylcholine receptors (more specifically Gi-coupled M2/M4 subtypes), dopamine receptors and opioid receptors. In addition to GPCRs, also phosphorylates various substrates: Hsc70-interacting protein/ST13, TP53/p53, HDAC5, and arrestin-1/ARRB1. Phosphorylation of ARRB1 by GRK5 inhibits G-protein independent MAPK1/MAPK3 signaling downstream of 5HT4-receptors. Phosphorylation of HDAC5, a repressor of myocyte enhancer factor 2 (MEF2) leading to nuclear export of HDAC5 and allowing MEF2-mediated transcription. Phosphorylation of TP53/p53, a crucial tumor suppressor, inhibits TP53/p53-mediated apoptosis. Phosphorylation of ST13 regulates internalization of the chemokine receptor. Phosphorylates rhodopsin (RHO) (in vitro) and a non G-protein-coupled receptor, LRP6 during Wnt signaling (in vitro).<ref>PMID:19661922</ref> <ref>PMID:19801552</ref> <ref>PMID:20038610</ref> <ref>PMID:20124405</ref> <ref>PMID:21728385</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 24: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Benovic, J L]]
+[[Category: Homo sapiens]]
-[[Category: Bhardwaj, A]]
+[[Category: Large Structures]]
-[[Category: Komolov, K E]]
+[[Category: Benovic JL]]
-[[Category: Gpcr kinase]]
+[[Category: Bhardwaj A]]
-[[Category: Grk5-sangivamycin complex]]
+[[Category: Komolov KE]]
-[[Category: Inhibitor]]
-[[Category: Kinase]]
-[[Category: Signaling protein]]

4tnb

From Proteopedia

Current revision

Crystal Structure of G Protein-Coupled Receptor Kinase 5 in Complex with Sangivamycin

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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