1bl7
From Proteopedia
(New page: 200px<br /> <applet load="1bl7" size="450" color="white" frame="true" align="right" spinBox="true" caption="1bl7, resolution 2.5Å" /> '''THE COMPLEX STRUCTUR...) |
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| - | [[Image:1bl7.gif|left|200px]]<br /> | + | [[Image:1bl7.gif|left|200px]]<br /><applet load="1bl7" size="350" color="white" frame="true" align="right" spinBox="true" |
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caption="1bl7, resolution 2.5Å" /> | caption="1bl7, resolution 2.5Å" /> | ||
'''THE COMPLEX STRUCTURE OF THE MAP KINASE P38/SB220025'''<br /> | '''THE COMPLEX STRUCTURE OF THE MAP KINASE P38/SB220025'''<br /> | ||
==Overview== | ==Overview== | ||
| - | BACKGROUND: The mitogen-activated protein (MAP) kinases are important | + | BACKGROUND: The mitogen-activated protein (MAP) kinases are important signaling molecules that participate in diverse cellular events and are potential targets for intervention in inflammation, cancer, and other diseases. The MAP kinase p38 is responsive to environmental stresses and is involved in the production of cytokines during inflammation. In contrast, the activation of the MAP kinase ERK2 (extracellular-signal-regulated kinase 2) leads to cellular differentiation or proliferation. The anti-inflammatory agent pyridinylimidazole and its analogs (SB [SmithKline Beecham] compounds) are highly potent and selective inhibitors of p38, but not of the closely-related ERK2, or other serine/threonine kinases. Although these compounds are known to bind to the ATP-binding site, the origin of the inhibitory specificity toward p38 is not clear. RESULTS: We report the structural basis for the exceptional selectivity of these SB compounds for p38 over ERK2, as determined by comparative crystallography. In addition, structural data on the origin of olomoucine (a better inhibitor of ERK2) selectivity are presented. The crystal structures of four SB compounds in complex with p38 and of one SB compound and olomoucine in complex with ERK2 are presented here. The SB inhibitors bind in an extended pocket in the active site and are complementary to the open domain structure of the low-activity form of p38. The relatively closed domain structure of ERK2 is able to accommodate the smaller olomoucine. CONCLUSIONS: The unique kinase-inhibitor interactions observed in these complexes originate from amino-acid replacements in the active site and replacements distant from the active site that affect the size of the domain interface. This structural information should facilitate the design of better MAP-kinase inhibitors for the treatment of inflammation and other diseases. |
==About this Structure== | ==About this Structure== | ||
| - | 1BL7 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 SB4 as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | + | 1BL7 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=SB4:'>SB4</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1BL7 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Abdel-Meguid, S.]] | [[Category: Abdel-Meguid, S.]] | ||
| - | [[Category: Adams, J | + | [[Category: Adams, J L.]] |
| - | [[Category: Boehm, J | + | [[Category: Boehm, J C.]] |
| - | [[Category: Canagarajah, B | + | [[Category: Canagarajah, B J.]] |
| - | [[Category: Cobb, M | + | [[Category: Cobb, M H.]] |
| - | [[Category: Goldsmith, E | + | [[Category: Goldsmith, E J.]] |
[[Category: Kassis, S.]] | [[Category: Kassis, S.]] | ||
[[Category: Wang, Z.]] | [[Category: Wang, Z.]] | ||
| - | [[Category: Young, P | + | [[Category: Young, P R.]] |
[[Category: SB4]] | [[Category: SB4]] | ||
[[Category: inhibitor]] | [[Category: inhibitor]] | ||
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[[Category: transferase]] | [[Category: transferase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 11:56:27 2008'' |
Revision as of 09:56, 21 February 2008
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THE COMPLEX STRUCTURE OF THE MAP KINASE P38/SB220025
Overview
BACKGROUND: The mitogen-activated protein (MAP) kinases are important signaling molecules that participate in diverse cellular events and are potential targets for intervention in inflammation, cancer, and other diseases. The MAP kinase p38 is responsive to environmental stresses and is involved in the production of cytokines during inflammation. In contrast, the activation of the MAP kinase ERK2 (extracellular-signal-regulated kinase 2) leads to cellular differentiation or proliferation. The anti-inflammatory agent pyridinylimidazole and its analogs (SB [SmithKline Beecham] compounds) are highly potent and selective inhibitors of p38, but not of the closely-related ERK2, or other serine/threonine kinases. Although these compounds are known to bind to the ATP-binding site, the origin of the inhibitory specificity toward p38 is not clear. RESULTS: We report the structural basis for the exceptional selectivity of these SB compounds for p38 over ERK2, as determined by comparative crystallography. In addition, structural data on the origin of olomoucine (a better inhibitor of ERK2) selectivity are presented. The crystal structures of four SB compounds in complex with p38 and of one SB compound and olomoucine in complex with ERK2 are presented here. The SB inhibitors bind in an extended pocket in the active site and are complementary to the open domain structure of the low-activity form of p38. The relatively closed domain structure of ERK2 is able to accommodate the smaller olomoucine. CONCLUSIONS: The unique kinase-inhibitor interactions observed in these complexes originate from amino-acid replacements in the active site and replacements distant from the active site that affect the size of the domain interface. This structural information should facilitate the design of better MAP-kinase inhibitors for the treatment of inflammation and other diseases.
About this Structure
1BL7 is a Single protein structure of sequence from Homo sapiens with as ligand. Full crystallographic information is available from OCA.
Reference
Structural basis of inhibitor selectivity in MAP kinases., Wang Z, Canagarajah BJ, Boehm JC, Kassisa S, Cobb MH, Young PR, Abdel-Meguid S, Adams JL, Goldsmith EJ, Structure. 1998 Sep 15;6(9):1117-28. PMID:9753691
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