A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics.
Activation of the ERK pathway is a hallmark of cancer, and targeting of upstream signaling partners led to the development of approved drugs. Recently, SCH772984 has been shown to be a selective and potent ERK1/2 inhibitor. Here we report the structural mechanism for its remarkable selectivity. In E...
| Үндсэн зохиолчид: | , , , , , , |
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| Формат: | Journal article |
| Хэл сонгох: | English |
| Хэвлэсэн: |
2014
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| _version_ | 1826262506885087232 |
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| author | Chaikuad, A Tacconi, E Zimmer, J Liang, Y Gray, N Tarsounas, M Knapp, S |
| author_facet | Chaikuad, A Tacconi, E Zimmer, J Liang, Y Gray, N Tarsounas, M Knapp, S |
| author_sort | Chaikuad, A |
| collection | OXFORD |
| description | Activation of the ERK pathway is a hallmark of cancer, and targeting of upstream signaling partners led to the development of approved drugs. Recently, SCH772984 has been shown to be a selective and potent ERK1/2 inhibitor. Here we report the structural mechanism for its remarkable selectivity. In ERK1/2, SCH772984 induces a so-far-unknown binding pocket that accommodates the piperazine-phenyl-pyrimidine decoration. This new binding pocket was created by an inactive conformation of the phosphate-binding loop and an outward tilt of helix αC. In contrast, structure determination of SCH772984 with the off-target haspin and JNK1 revealed two canonical but distinct type I binding modes. Notably, the new binding mode with ERK1/2 was associated with slow binding kinetics in vitro as well as in cell-based assay systems. The described binding mode of SCH772984 with ERK1/2 enables the design of a new type of specific kinase inhibitors with prolonged on-target activity. |
| first_indexed | 2024-03-06T19:37:15Z |
| format | Journal article |
| id | oxford-uuid:1f7539cd-9b0b-4d68-9c21-0dfbdcfa4441 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T19:37:15Z |
| publishDate | 2014 |
| record_format | dspace |
| spelling | oxford-uuid:1f7539cd-9b0b-4d68-9c21-0dfbdcfa44412022-03-26T11:21:57ZA unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:1f7539cd-9b0b-4d68-9c21-0dfbdcfa4441EnglishSymplectic Elements at Oxford2014Chaikuad, ATacconi, EZimmer, JLiang, YGray, NTarsounas, MKnapp, SActivation of the ERK pathway is a hallmark of cancer, and targeting of upstream signaling partners led to the development of approved drugs. Recently, SCH772984 has been shown to be a selective and potent ERK1/2 inhibitor. Here we report the structural mechanism for its remarkable selectivity. In ERK1/2, SCH772984 induces a so-far-unknown binding pocket that accommodates the piperazine-phenyl-pyrimidine decoration. This new binding pocket was created by an inactive conformation of the phosphate-binding loop and an outward tilt of helix αC. In contrast, structure determination of SCH772984 with the off-target haspin and JNK1 revealed two canonical but distinct type I binding modes. Notably, the new binding mode with ERK1/2 was associated with slow binding kinetics in vitro as well as in cell-based assay systems. The described binding mode of SCH772984 with ERK1/2 enables the design of a new type of specific kinase inhibitors with prolonged on-target activity. |
| spellingShingle | Chaikuad, A Tacconi, E Zimmer, J Liang, Y Gray, N Tarsounas, M Knapp, S A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics. |
| title | A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics. |
| title_full | A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics. |
| title_fullStr | A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics. |
| title_full_unstemmed | A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics. |
| title_short | A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics. |
| title_sort | unique inhibitor binding site in erk1 2 is associated with slow binding kinetics |
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