1q8w
From Proteopedia
(New page: 200px<br /><applet load="1q8w" size="450" color="white" frame="true" align="right" spinBox="true" caption="1q8w, resolution 2.20Å" /> '''The Catalytic Subuni...) |
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| - | [[Image:1q8w.jpg|left|200px]]<br /><applet load="1q8w" size=" | + | [[Image:1q8w.jpg|left|200px]]<br /><applet load="1q8w" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1q8w, resolution 2.20Å" /> | caption="1q8w, resolution 2.20Å" /> | ||
'''The Catalytic Subunit of cAMP-dependent Protein Kinase in Complex with Rho-kinase Inhibitor Fasudil (HA-1077)'''<br /> | '''The Catalytic Subunit of cAMP-dependent Protein Kinase in Complex with Rho-kinase Inhibitor Fasudil (HA-1077)'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Protein kinases require strict inactivation to prevent spurious cellular | + | Protein kinases require strict inactivation to prevent spurious cellular signaling; overactivity can cause cancer or other diseases and necessitates selective inhibition for therapy. Rho-kinase is involved in such processes as tumor invasion, cell adhesion, smooth muscle contraction, and formation of focal adhesion fibers, as revealed using inhibitor Y-27632. Another Rho-kinase inhibitor, HA-1077 or Fasudil, is currently used in the treatment of cerebral vasospasm; the related nanomolar inhibitor H-1152P improves on its selectivity and potency. We have determined the crystal structures of HA-1077, H-1152P, and Y-27632 in complexes with protein kinase A (PKA) as a surrogate kinase to analyze Rho-kinase inhibitor binding properties. Features conserved between PKA and Rho-kinase are involved in the key binding interactions, while a combination of residues at the ATP binding pocket that are unique to Rho-kinase may explain the inhibitors' Rho-kinase selectivity. Further, a second H-1152P binding site potentially points toward PKA regulatory domain interaction modulators. |
==About this Structure== | ==About this Structure== | ||
| - | 1Q8W is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] with M77 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:// | + | 1Q8W is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] with <scene name='pdbligand=M77:'>M77</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=1Q8W OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Bossemeyer, D.]] | [[Category: Bossemeyer, D.]] | ||
[[Category: Breitenlechner, C.]] | [[Category: Breitenlechner, C.]] | ||
| - | [[Category: Engh, R | + | [[Category: Engh, R A.]] |
[[Category: Gassel, M.]] | [[Category: Gassel, M.]] | ||
[[Category: Hidaka, H.]] | [[Category: Hidaka, H.]] | ||
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[[Category: serine/threonine-protein kinase]] | [[Category: serine/threonine-protein kinase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:37:06 2008'' |
Revision as of 12:37, 21 February 2008
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The Catalytic Subunit of cAMP-dependent Protein Kinase in Complex with Rho-kinase Inhibitor Fasudil (HA-1077)
Overview
Protein kinases require strict inactivation to prevent spurious cellular signaling; overactivity can cause cancer or other diseases and necessitates selective inhibition for therapy. Rho-kinase is involved in such processes as tumor invasion, cell adhesion, smooth muscle contraction, and formation of focal adhesion fibers, as revealed using inhibitor Y-27632. Another Rho-kinase inhibitor, HA-1077 or Fasudil, is currently used in the treatment of cerebral vasospasm; the related nanomolar inhibitor H-1152P improves on its selectivity and potency. We have determined the crystal structures of HA-1077, H-1152P, and Y-27632 in complexes with protein kinase A (PKA) as a surrogate kinase to analyze Rho-kinase inhibitor binding properties. Features conserved between PKA and Rho-kinase are involved in the key binding interactions, while a combination of residues at the ATP binding pocket that are unique to Rho-kinase may explain the inhibitors' Rho-kinase selectivity. Further, a second H-1152P binding site potentially points toward PKA regulatory domain interaction modulators.
About this Structure
1Q8W is a Protein complex structure of sequences from Bos taurus 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.
Reference
Protein kinase A in complex with Rho-kinase inhibitors Y-27632, Fasudil, and H-1152P: structural basis of selectivity., Breitenlechner C, Gassel M, Hidaka H, Kinzel V, Huber R, Engh RA, Bossemeyer D, Structure. 2003 Dec;11(12):1595-607. PMID:14656443
Page seeded by OCA on Thu Feb 21 14:37:06 2008
Categories: Bos taurus | Non-specific serine/threonine protein kinase | Protein complex | Bossemeyer, D. | Breitenlechner, C. | Engh, R A. | Gassel, M. | Hidaka, H. | Huber, R. | Kinzel, V. | M77 | Atp-binding | Camp | Kinase-inhibitor-complex | Phosphorylation | Phosphotransferase/inhibitor | Pka | Rho-kinase | Serine/threonine-protein kinase
