2hw6: Difference between revisions
New page: left|200px<br /> <applet load="2hw6" size="450" color="white" frame="true" align="right" spinBox="true" caption="2hw6, resolution 2.50Å" /> '''Crystal structure o... |
No edit summary |
||
| Line 1: | Line 1: | ||
[[Image:2hw6.gif|left|200px]]<br /> | [[Image:2hw6.gif|left|200px]]<br /><applet load="2hw6" size="350" color="white" frame="true" align="right" spinBox="true" | ||
<applet load="2hw6" size=" | |||
caption="2hw6, resolution 2.50Å" /> | caption="2hw6, resolution 2.50Å" /> | ||
'''Crystal structure of Mnk1 catalytic domain'''<br /> | '''Crystal structure of Mnk1 catalytic domain'''<br /> | ||
==Overview== | ==Overview== | ||
Autoinhibition is a recurring mode of protein kinase regulation and can be | Autoinhibition is a recurring mode of protein kinase regulation and can be based on diverse molecular mechanisms. Here, we show by crystal structure analysis, nuclear magnetic resonance (NMR)-based nucleotide affinity studies and rational mutagenesis that nonphosphorylated mitogen-activated protein (MAP) kinases interacting kinase (Mnk) 1 is autoinhibited by conversion of the activation segment into an autoinhibitory module. In a Mnk1 crystal structure, the activation segment is repositioned via a Mnk-specific sequence insertion at the N-terminal lobe with the following consequences: (i) the peptide substrate binding site is deconstructed, (ii) the interlobal cleft is narrowed, (iii) an essential Lys-Glu pair is disrupted and (iv) the magnesium-binding loop is locked into an ATP-competitive conformation. Consistently, deletion of the Mnk-specific insertion or removal of a conserved phenylalanine side chain, which induces a blockade of the ATP pocket, increase the ATP affinity of Mnk1. Structural rearrangements required for the activation of Mnks are apparent from the cocrystal structure of a Mnk2 D228G -staurosporine complex and can be modeled on the basis of crystal packing interactions. Our data suggest a novel regulatory mechanism specific for the Mnk subfamily. | ||
==About this Structure== | ==About this Structure== | ||
2HW6 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with SO4 as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] Full crystallographic information is available from [http:// | 2HW6 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SO4:'>SO4</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2HW6 OCA]. | ||
==Reference== | ==Reference== | ||
| Line 16: | Line 15: | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Jauch, R.]] | [[Category: Jauch, R.]] | ||
[[Category: Wahl, M | [[Category: Wahl, M C.]] | ||
[[Category: SO4]] | [[Category: SO4]] | ||
[[Category: drug design]] | [[Category: drug design]] | ||
| Line 23: | Line 22: | ||
[[Category: protein kinase]] | [[Category: protein kinase]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:46:22 2008'' | ||
Revision as of 18:46, 21 February 2008
|
Crystal structure of Mnk1 catalytic domain
OverviewOverview
Autoinhibition is a recurring mode of protein kinase regulation and can be based on diverse molecular mechanisms. Here, we show by crystal structure analysis, nuclear magnetic resonance (NMR)-based nucleotide affinity studies and rational mutagenesis that nonphosphorylated mitogen-activated protein (MAP) kinases interacting kinase (Mnk) 1 is autoinhibited by conversion of the activation segment into an autoinhibitory module. In a Mnk1 crystal structure, the activation segment is repositioned via a Mnk-specific sequence insertion at the N-terminal lobe with the following consequences: (i) the peptide substrate binding site is deconstructed, (ii) the interlobal cleft is narrowed, (iii) an essential Lys-Glu pair is disrupted and (iv) the magnesium-binding loop is locked into an ATP-competitive conformation. Consistently, deletion of the Mnk-specific insertion or removal of a conserved phenylalanine side chain, which induces a blockade of the ATP pocket, increase the ATP affinity of Mnk1. Structural rearrangements required for the activation of Mnks are apparent from the cocrystal structure of a Mnk2 D228G -staurosporine complex and can be modeled on the basis of crystal packing interactions. Our data suggest a novel regulatory mechanism specific for the Mnk subfamily.
About this StructureAbout this Structure
2HW6 is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Full crystallographic information is available from OCA.
ReferenceReference
Mitogen-activated protein kinases interacting kinases are autoinhibited by a reprogrammed activation segment., Jauch R, Cho MK, Jakel S, Netter C, Schreiter K, Aicher B, Zweckstetter M, Jackle H, Wahl MC, EMBO J. 2006 Sep 6;25(17):4020-32. Epub 2006 Aug 17. PMID:16917500
Page seeded by OCA on Thu Feb 21 17:46:22 2008