2hen
From Proteopedia
(New page: 200px<br /><applet load="2hen" size="450" color="white" frame="true" align="right" spinBox="true" caption="2hen, resolution 2.60Å" /> '''Crystal Structure of...) |
|||
| Line 1: | Line 1: | ||
| - | [[Image:2hen.jpg|left|200px]]<br /><applet load="2hen" size=" | + | [[Image:2hen.jpg|left|200px]]<br /><applet load="2hen" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="2hen, resolution 2.60Å" /> | caption="2hen, resolution 2.60Å" /> | ||
'''Crystal Structure of the EphB2 Receptor Kinase domain in complex with ADP'''<br /> | '''Crystal Structure of the EphB2 Receptor Kinase domain in complex with ADP'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Eph receptor tyrosine kinases (RTKs) mediate numerous developmental | + | Eph receptor tyrosine kinases (RTKs) mediate numerous developmental processes. Their activity is regulated by auto-phosphorylation on two tyrosines within the juxtamembrane segment (JMS) immediately N-terminal to the kinase domain (KD). Here, we probe the molecular details of Eph kinase activation through mutational analysis, X-ray crystallography and NMR spectroscopy on auto-inhibited and active EphB2 and EphA4 fragments. We show that a Tyr750Ala gain-of-function mutation in the KD and JMS phosphorylation independently induce disorder of the JMS and its dissociation from the KD. Our X-ray analyses demonstrate that this occurs without major conformational changes to the KD and with only partial ordering of the KD activation segment. However, conformational exchange for helix alphaC in the N-terminal KD lobe and for the activation segment, coupled with increased inter-lobe dynamics, is observed upon kinase activation in our NMR analyses. Overall, our results suggest that a change in inter-lobe dynamics and the sampling of catalytically competent conformations for helix alphaC and the activation segment rather than a transition to a static active conformation underlies Eph RTK activation. |
==About this Structure== | ==About this Structure== | ||
| - | 2HEN is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with MG and ADP as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] Full crystallographic information is available from [http:// | + | 2HEN is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with <scene name='pdbligand=MG:'>MG</scene> and <scene name='pdbligand=ADP:'>ADP</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2HEN OCA]. |
==Reference== | ==Reference== | ||
| Line 16: | Line 16: | ||
[[Category: Pawson, T.]] | [[Category: Pawson, T.]] | ||
[[Category: Sicheri, F.]] | [[Category: Sicheri, F.]] | ||
| - | [[Category: Wybenga-Groot, L | + | [[Category: Wybenga-Groot, L E.]] |
[[Category: ADP]] | [[Category: ADP]] | ||
[[Category: MG]] | [[Category: MG]] | ||
| Line 22: | Line 22: | ||
[[Category: eph kinase domain]] | [[Category: eph kinase domain]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:41:04 2008'' |
Revision as of 15:41, 21 February 2008
|
Crystal Structure of the EphB2 Receptor Kinase domain in complex with ADP
Overview
Eph receptor tyrosine kinases (RTKs) mediate numerous developmental processes. Their activity is regulated by auto-phosphorylation on two tyrosines within the juxtamembrane segment (JMS) immediately N-terminal to the kinase domain (KD). Here, we probe the molecular details of Eph kinase activation through mutational analysis, X-ray crystallography and NMR spectroscopy on auto-inhibited and active EphB2 and EphA4 fragments. We show that a Tyr750Ala gain-of-function mutation in the KD and JMS phosphorylation independently induce disorder of the JMS and its dissociation from the KD. Our X-ray analyses demonstrate that this occurs without major conformational changes to the KD and with only partial ordering of the KD activation segment. However, conformational exchange for helix alphaC in the N-terminal KD lobe and for the activation segment, coupled with increased inter-lobe dynamics, is observed upon kinase activation in our NMR analyses. Overall, our results suggest that a change in inter-lobe dynamics and the sampling of catalytically competent conformations for helix alphaC and the activation segment rather than a transition to a static active conformation underlies Eph RTK activation.
About this Structure
2HEN is a Single protein structure of sequence from Mus musculus with and as ligands. Active as Receptor protein-tyrosine kinase, with EC number 2.7.10.1 Full crystallographic information is available from OCA.
Reference
A change in conformational dynamics underlies the activation of Eph receptor tyrosine kinases., Wiesner S, Wybenga-Groot LE, Warner N, Lin H, Pawson T, Forman-Kay JD, Sicheri F, EMBO J. 2006 Oct 4;25(19):4686-96. Epub 2006 Sep 14. PMID:16977320
Page seeded by OCA on Thu Feb 21 17:41:04 2008
