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Related Concept Videos

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Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
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Microtubule function and architecture are regulated by an array of specialized proteins called microtubule-associated proteins or MAPs. These proteins are widespread across different organisms and have conserved protein motifs, like the multi-TOG domain for tubulin binding found in the CLASP family of MAPs. Some MAPs are lineage-specific based on their conserved domains. Their functions depend upon the cytoskeletal architecture and cell type they are located within. In-plant cells, a specific...
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The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
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Related Experiment Video

Updated: Dec 9, 2025

Identification of Kinase-substrate Pairs Using High Throughput Screening
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Structural basis for producing selective MAP2K7 inhibitors.

Yuka Murakawa1, Shirly Valter2, Haim Barr2

  • 1Graduate School of Science, Osaka Prefecture University, Osaka 599-8531, Japan.

Bioorganic & Medicinal Chemistry Letters
|September 15, 2020
PubMed
Summary
This summary is machine-generated.

Mitogen-activated protein kinase kinase 7 (MAP2K7) inhibitors are key drug targets. A new crystal structure reveals how covalent inhibitors achieve selectivity, overcoming a major drug development hurdle.

Keywords:
Covalent bonding inhibitorMAP2K7SelectivityStructural flexibility

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Area of Science:

  • Biochemistry
  • Structural Biology
  • Drug Discovery

Background:

  • Mitogen-activated protein kinase kinase 7 (MAP2K7) is a crucial component of the c-Jun N-terminal kinase (JNK) signaling pathway.
  • The JNK pathway plays a significant role in various disease states, making MAP2K7 a promising therapeutic target.
  • Developing selective inhibitors for MAP2K7 is challenging due to potential off-target kinase activity, hindering drug development.

Purpose of the Study:

  • To elucidate the structural basis for the selectivity and potency of MAP2K7 inhibitors.
  • To provide insights for the rational design of novel MAP2K7-targeted therapeutics.
  • To address the critical barrier of off-target kinase inhibition in MAP2K7 drug development.

Main Methods:

  • X-ray crystallography was employed to determine the structure of MAP2K7.
  • The crystal structure was obtained for MAP2K7 in complex with a potent covalent inhibitor.
  • The inhibitor featured an acrylamide moiety acting as an electrophile.

Main Results:

  • A high-resolution crystal structure of MAP2K7 bound to a covalent inhibitor was successfully determined.
  • The structure revealed specific interactions between the inhibitor and MAP2K7, explaining the observed potency.
  • The binding mode provided insights into the mechanism of selectivity against other kinases.
  • The acrylamide electrophile was identified as a key feature for covalent binding and selectivity.

Conclusions:

  • The determined crystal structure provides a detailed molecular understanding of MAP2K7 inhibition.
  • This structural information serves as a foundation for designing more selective and potent MAP2K7 inhibitors.
  • The findings facilitate the advancement of MAP2K7-targeted therapies for various diseases.