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==Crystal structure of the DnaK C-terminus (Dnak-SBD-A)==
==Crystal structure of the DnaK C-terminus (Dnak-SBD-A)==
<StructureSection load='4r5j' size='340' side='right' caption='[[4r5j]], [[Resolution|resolution]] 2.36&Aring;' scene=''>
<StructureSection load='4r5j' size='340' side='right'caption='[[4r5j]], [[Resolution|resolution]] 2.36&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4r5j]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4R5J OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4R5J FirstGlance]. <br>
<table><tr><td colspan='2'>[[4r5j]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4R5J OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4R5J FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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]] 2.361&#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=4r5j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r5j OCA], [http://pdbe.org/4r5j PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4r5j RCSB], [http://www.ebi.ac.uk/pdbsum/4r5j PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4r5j ProSAT]</span></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>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=4r5j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r5j OCA], [https://pdbe.org/4r5j PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4r5j RCSB], [https://www.ebi.ac.uk/pdbsum/4r5j PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4r5j ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/DNAK_ECOLI DNAK_ECOLI]] Plays an essential role in the initiation of phage lambda DNA replication, where it acts in an ATP-dependent fashion with the DnaJ protein to release lambda O and P proteins from the preprimosomal complex. DnaK is also involved in chromosomal DNA replication, possibly through an analogous interaction with the DnaA protein. Also participates actively in the response to hyperosmotic shock.[HAMAP-Rule:MF_00332]  
[https://www.uniprot.org/uniprot/DNAK_ECOLI DNAK_ECOLI] Plays an essential role in the initiation of phage lambda DNA replication, where it acts in an ATP-dependent fashion with the DnaJ protein to release lambda O and P proteins from the preprimosomal complex. DnaK is also involved in chromosomal DNA replication, possibly through an analogous interaction with the DnaA protein. Also participates actively in the response to hyperosmotic shock.[HAMAP-Rule:MF_00332]
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The stress-inducible mammalian heat shock protein 70 (HSP70) and its bacterial orthologue DnaK are highly conserved nucleotide binding molecular chaperones. They represent critical regulators of cellular proteostasis, especially during conditions of enhanced stress. Cancer cells rely on HSP70 for survival, and this chaperone represents an attractive new therapeutic target. We have used a structure-activity approach and biophysical methods to characterize a class of inhibitors that bind to a unique allosteric site within the C-terminus of HSP70 and DnaK. Data from X-ray crystallography together with isothermal titration calorimetry, mutagenesis, and cell-based assays indicate that these inhibitors bind to a previously unappreciated allosteric pocket formed within the non-ATP-bound protein state. Moreover, binding of inhibitor alters the local protein conformation, resulting in reduced chaperone-client interactions and impairment of proteostasis. Our findings thereby provide a new chemical scaffold and target platform for both HSP70 and DnaK; these will be important tools with which to interrogate chaperone function and to aid ongoing efforts to optimize potency and efficacy in developing modulators of these chaperones for therapeutic use.
 
Structural Basis for the Inhibition of HSP70 and DnaK Chaperones by Small-Molecule Targeting of a C-Terminal Allosteric Pocket.,Leu JI, Zhang P, Murphy ME, Marmorstein R, George DL ACS Chem Biol. 2014 Aug 28. PMID:25148104<ref>PMID:25148104</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4r5j" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[Heat Shock Proteins|Heat Shock Proteins]]
*[[Heat Shock Protein structures|Heat Shock Protein structures]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: George, D L]]
[[Category: Escherichia coli K-12]]
[[Category: Leu, J I]]
[[Category: Large Structures]]
[[Category: Marmorstein, R]]
[[Category: George DL]]
[[Category: Murphy, M E]]
[[Category: Leu JI]]
[[Category: Zhang, P]]
[[Category: Marmorstein R]]
[[Category: Beta sheet]]
[[Category: Murphy ME]]
[[Category: Chaperone]]
[[Category: Zhang P]]
[[Category: Helical bundle]]
[[Category: Membrane]]

Latest revision as of 12:50, 1 March 2024

Crystal structure of the DnaK C-terminus (Dnak-SBD-A)

4r5j, resolution 2.36Å

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