3C9W

Crystal Structure of ERK-2 with hypothemycin covalently bound

Summary for 3C9W

• Entry DOI: 10.2210/pdb3c9w/pdb
• Related: 1ERK 2E14
• Descriptor: Mitogen-activated protein kinase 1, (1aR,8S,13S,14S,15aR)-5,13,14-trihydroxy-3-methoxy-8-methyl-8,9,13,14,15,15a-hexahydro-6H-oxireno[k][2]benzoxacyclotetradecine-6,12(1aH)-dione (3 entities in total)
• Functional Keywords: erk, acetylation, atp-binding, cell cycle, kinase, nucleotide-binding, phosphoprotein, serine/threonine-protein kinase, transferase
• Biological source: Rattus norvegicus (Rat)
• Cellular location: Cytoplasm, cytoskeleton, spindle : P63086
• Total number of polymer chains: 2
• Total formula weight: 83155.46

Authors

Rosenfeld, R.J. (deposition date: 2008-02-18, release date: 2008-07-08, Last modification date: 2024-11-06)

Primary citation

Rastelli, G.,Rosenfeld, R.,Reid, R.,Santi, D.V.
Molecular modeling and crystal structure of ERK2-hypothemycin complexes
J.Struct.Biol., 164:18-23, 2008

PubMed Abstract: Resorcylic acid lactones containing a cis-enone-such as hypothemycin-are susceptible to Michael addition reactions and are potent and specific inhibitors of about 45 of the known Ser/Thr/Tyr protein kinases. These inhibitors bind reversibly, and then form a covalent adduct with a completely conserved cysteine in the ATP binding site of their target kinases. As a paradigm for the structures of the cis-enone resorcylic acid lactone complexes with this subset of kinases, we have modeled the structure of ERK2-hypothemycin reversible and covalent complexes using docking and extended molecular dynamics simulations. Subsequently, we determined the 2.5A resolution crystal structure of the complex that was in excellent accord with the modeled structure. The results were used to discuss structure-activity relationships, and provide a structural template for the development of irreversible inhibitors that complement the ATP binding site of kinases.

PubMed: 18571434
DOI: 10.1016/j.jsb.2008.05.002

Experimental method

X-RAY DIFFRACTION (2.5 Å)