3QFV

MRCK beta in complex with TPCA-1

3QFV の概要

• エントリーDOI: 10.2210/pdb3qfv/pdb
• 関連するPDBエントリー: 3MY4
• 分子名称: CDC42BPB protein, 2-(carbamoylamino)-5-(4-fluorophenyl)thiophene-3-carboxamide, 1,2-ETHANEDIOL, ... (6 entities in total)
• 機能のキーワード: protein kinase domain of mrck beta in complex with tpca-1, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 96314.24

構造登録者

Heikkila, T.J.,Wheatley, E.,Crighton, D.,Schroder, E.,Boakes, A.,Kaye, S.J.,Mezna, M.,Pang, L.,Rushbrooke, M.,Turnbull, A.,Olson, M.F. (登録日: 2011-01-23, 公開日: 2011-10-12, 最終更新日: 2026-03-04)

主引用文献

Heikkila, T.,Wheatley, E.,Crighton, D.,Schroder, E.,Boakes, A.,Kaye, S.J.,Mezna, M.,Pang, L.,Rushbrooke, M.,Turnbull, A.,Olson, M.F.
Co-crystal structures of inhibitors with MRCK beta , a key regulator of tumor cell invasion.
Plos One, 6:e24825-e24825, 2011

PubMed Abstract: MRCKα and MRCKβ (myotonic dystrophy kinase-related Cdc42-binding kinases) belong to a subfamily of Rho GTPase activated serine/threonine kinases within the AGC-family that regulate the actomyosin cytoskeleton. Reflecting their roles in myosin light chain (MLC) phosphorylation, MRCKα and MRCKβ influence cell shape and motility. We report further evidence for MRCKα and MRCKβ contributions to the invasion of cancer cells in 3-dimensional matrix invasion assays. In particular, our results indicate that the combined inhibition of MRCKα and MRCKβ together with inhibition of ROCK kinases results in significantly greater effects on reducing cancer cell invasion than blocking either MRCK or ROCK kinases alone. To probe the kinase ligand pocket, we screened 159 kinase inhibitors in an in vitro MRCKβ kinase assay and found 11 compounds that inhibited enzyme activity >80% at 3 µM. Further analysis of three hits, Y-27632, Fasudil and TPCA-1, revealed low micromolar IC(50) values for MRCKα and MRCKβ. We also describe the crystal structure of MRCKβ in complex with inhibitors Fasudil and TPCA-1 bound to the active site of the kinase. These high-resolution structures reveal a highly conserved AGC kinase fold in a typical dimeric arrangement. The kinase domain is in an active conformation with a fully-ordered and correctly positioned αC helix and catalytic residues in a conformation competent for catalysis. Together, these results provide further validation for MRCK involvement in regulation of cancer cell invasion and present a valuable starting point for future structure-based drug discovery efforts.

PubMed: 21949762
DOI: 10.1371/journal.pone.0024825

実験手法

X-RAY DIFFRACTION (2.65 Å)