2zej
From Proteopedia
(New page: 200px<br /><applet load="2zej" size="350" color="white" frame="true" align="right" spinBox="true" caption="2zej, resolution 2.00Å" /> '''Structure of the ROC...) |
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caption="2zej, resolution 2.00Å" /> | caption="2zej, resolution 2.00Å" /> | ||
'''Structure of the ROC domain from the Parkinson's disease-associated leucine-rich repeat kinase 2 reveals a dimeric GTPase'''<br /> | '''Structure of the ROC domain from the Parkinson's disease-associated leucine-rich repeat kinase 2 reveals a dimeric GTPase'''<br /> | ||
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| + | ==Overview== | ||
| + | Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common, cause of Parkinson's disease (PD). LRRK2 contains a Ras of complex, proteins (ROC) domain that may act as a GTPase to regulate its protein, kinase activity. The structure of ROC and the mechanism(s) by which it, regulates kinase activity are not known. Here, we report the crystal, structure of the LRRK2 ROC domain in complex with GDP-Mg(2+) at 2.0-A, resolution. The structure displays a dimeric fold generated by extensive, domain-swapping, resulting in a pair of active sites constructed with, essential functional groups contributed from both monomers. Two, PD-associated pathogenic residues, R1441 and I1371, are located at the, interface of two monomers and provide exquisite interactions to stabilize, the ROC dimer. The structure demonstrates that loss of stabilizing forces, in the ROC dimer is likely related to decreased GTPase activity resulting, from mutations at these sites. Our data suggest that the ROC domain may, regulate LRRK2 kinase activity as a dimer, possibly via the C-terminal of, ROC (COR) domain as a molecular hinge. The structure of the LRRK2 ROC, domain also represents a signature from a previously undescribed class of, GTPases from complex proteins and results may provide a unique molecular, target for therapeutics in PD. | ||
==About this Structure== | ==About this Structure== | ||
| - | 2ZEJ 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=MG:'>MG</scene> and <scene name='pdbligand=GDP:'>GDP</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. 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=2ZEJ OCA]. | + | 2ZEJ 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=MG:'>MG</scene> and <scene name='pdbligand=GDP:'>GDP</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. 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] Known structural/functional Sites: <scene name='pdbsite=AC1:Mg+Binding+Site+For+Residue+A+2'>AC1</scene>, <scene name='pdbsite=AC2:Mg+Binding+Site+For+Residue+B+1'>AC2</scene>, <scene name='pdbsite=AC3:Gdp+Binding+Site+For+Residue+A+1'>AC3</scene> and <scene name='pdbsite=AC4:Gdp+Binding+Site+For+Residue+B+2'>AC4</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ZEJ OCA]. |
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| + | ==Reference== | ||
| + | Structure of the ROC domain from the Parkinson's disease-associated leucine-rich repeat kinase 2 reveals a dimeric GTPase., Deng J, Lewis PA, Greggio E, Sluch E, Beilina A, Cookson MR, Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1499-504. Epub 2008 Jan 29. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=18230735 18230735] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Non-specific serine/threonine protein kinase]] | [[Category: Non-specific serine/threonine protein kinase]] | ||
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[[Category: transferase]] | [[Category: transferase]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Feb 13 08:18:42 2008'' |
Revision as of 06:18, 13 February 2008
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Structure of the ROC domain from the Parkinson's disease-associated leucine-rich repeat kinase 2 reveals a dimeric GTPase
Overview
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common, cause of Parkinson's disease (PD). LRRK2 contains a Ras of complex, proteins (ROC) domain that may act as a GTPase to regulate its protein, kinase activity. The structure of ROC and the mechanism(s) by which it, regulates kinase activity are not known. Here, we report the crystal, structure of the LRRK2 ROC domain in complex with GDP-Mg(2+) at 2.0-A, resolution. The structure displays a dimeric fold generated by extensive, domain-swapping, resulting in a pair of active sites constructed with, essential functional groups contributed from both monomers. Two, PD-associated pathogenic residues, R1441 and I1371, are located at the, interface of two monomers and provide exquisite interactions to stabilize, the ROC dimer. The structure demonstrates that loss of stabilizing forces, in the ROC dimer is likely related to decreased GTPase activity resulting, from mutations at these sites. Our data suggest that the ROC domain may, regulate LRRK2 kinase activity as a dimer, possibly via the C-terminal of, ROC (COR) domain as a molecular hinge. The structure of the LRRK2 ROC, domain also represents a signature from a previously undescribed class of, GTPases from complex proteins and results may provide a unique molecular, target for therapeutics in PD.
About this Structure
2ZEJ is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Known structural/functional Sites: , , and . Full crystallographic information is available from OCA.
Reference
Structure of the ROC domain from the Parkinson's disease-associated leucine-rich repeat kinase 2 reveals a dimeric GTPase., Deng J, Lewis PA, Greggio E, Sluch E, Beilina A, Cookson MR, Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1499-504. Epub 2008 Jan 29. PMID:18230735
Page seeded by OCA on Wed Feb 13 08:18:42 2008
Categories: Homo sapiens | Non-specific serine/threonine protein kinase | Single protein | Deng, J. | GDP | MG | Atp-binding | Coiled coil | Cytoplasm | Disease mutation | Gtp-binding | Gtpase | Gtpase activation | Kinase | Leucine-rich repeat | Lrrk2 | Membrane | Nucleotide-binding | Parkinson disease | Parkinson's disease | Polymorphism | Roc | Roco | Serine/threonine-protein kinase | Transferase
