View source for 4c59


==Structure of GAK kinase in complex with nanobody (NbGAK_4)==
<StructureSection load='4c59' size='340' side='right'caption='[[4c59]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4c59]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Lama_glama Lama glama]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4C59 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4C59 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]] 2.8&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FEF:(2Z,3E)-2,3-BIINDOLE-2,3(1H,1H)-DIONE+3-{O-[(3R)-3,4-DIHYDROXYBUTYL]OXIME}'>FEF</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=4c59 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c59 OCA], [https://pdbe.org/4c59 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4c59 RCSB], [https://www.ebi.ac.uk/pdbsum/4c59 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4c59 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/GAK_HUMAN GAK_HUMAN] Associates with cyclin G and CDK5. Seems to act as an auxilin homolog that is involved in the uncoating of clathrin-coated vesicles by Hsc70 in non-neuronal cells. Expression oscillates slightly during the cell cycle, peaking at G1.<ref>PMID:10625686</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
GAK (cyclin G-associated kinase) is a key regulator of clathrin-coated vesicle trafficking and plays a central role during development. Additionally, due to the unusually high plasticity of its catalytic domain, it is a frequent 'off-target' of clinical kinase inhibitors associated with respiratory side effects of these drugs. In the present paper, we determined the crystal structure of the GAK catalytic domain alone and in complex with specific single-chain antibodies (nanobodies). GAK is constitutively active and weakly associates in solution. The GAK apo structure revealed a dimeric inactive state of the catalytic domain mediated by an unusual activation segment interaction. Co-crystallization with the nanobody NbGAK_4 trapped GAK in a dimeric arrangement similar to the one observed in the apo structure, whereas NbGAK_1 captured the activation segment of monomeric GAK in a well-ordered conformation, representing features of the active kinase. The presented structural and biochemical data provide insight into the domain plasticity of GAK and demonstrate the utility of nanobodies to gain insight into conformational changes of dynamic molecules. In addition, we present structural data on the binding mode of ATP mimetic inhibitors and enzyme kinetic data, which will support rational inhibitor design of inhibitors to reduce the off-target effect on GAK.

Structure of cyclin G-associated kinase (GAK) trapped in different conformations using nanobodies.,Chaikuad A, Keates T, Vincke C, Kaufholz M, Zenn M, Zimmermann B, Gutierrez C, Zhang RG, Hatzos-Skintges C, Joachimiak A, Muyldermans S, Herberg FW, Knapp S, Muller S Biochem J. 2014 Apr 1;459(1):59-69. doi: 10.1042/BJ20131399. PMID:24438162<ref>PMID:24438162</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4c59" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Lama glama]]
[[Category: Large Structures]]
[[Category: Allerston CK]]
[[Category: Arrowsmith CH]]
[[Category: Bountra C]]
[[Category: Chaikuad A]]
[[Category: Edwards AM]]
[[Category: Gileadi O]]
[[Category: Keates T]]
[[Category: Knapp S]]
[[Category: Muller-Knapp S]]
[[Category: Von Delft F]]