PDBsum entry 5eak

Transferase/transferase inhibitor

PDB id: 5eak

Contents

Protein chains

305 a.a.

Ligands

24R ×2

Waters ×6

PDB id:

5eak

Name:

Transferase/transferase inhibitor

Title:

Optimization of microtubule affinity regulating kinase (mark) inhibitors with improved physical properties

Structure:

Serine/threonine-protein kinase mark2. Chain: a, b. Fragment: catalytic domain (unp residues 39-364). Synonym: elkl motif kinase 1,emk-1,map/microtubule affinity- regulating kinase 2,par1 homolog,par1 homolog b,par1b. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: mark2, emk1. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

2.80Å R-factor: 0.198 R-free: 0.254

Authors:

H.P.Su

Key ref:

D.L.Sloman et al. (2016). Optimization of microtubule affinity regulating kinase (MARK) inhibitors with improved physical properties. Bioorg Med Chem Lett, 26, 4362-4366. PubMed id: 27491711 DOI: 10.1016/j.bmcl.2016.02.003

Date:

16-Oct-15 Release date: 17-Feb-16

Protein chains

Q7KZI7  (MARK2_HUMAN) -  Serine/threonine-protein kinase MARK2 from Homo sapiens

Seq: 788 a.a.

Struc: 305 a.a.

Enzyme reactions

• Enzyme class 1: E.C.2.7.11.1 - non-specific serine/threonine protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺
• Enzyme class 2: E.C.2.7.11.26 - [tau protein] kinase.
• Reaction:
  1. L-seryl-[tau protein] + ATP = O-phospho-L-seryl-[tau protein] + ADP + H⁺
  2. L-threonyl-[tau protein] + ATP = O-phospho-L-threonyl-[tau protein] + ADP + H⁺

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1016/j.bmcl.2016.02.003

Bioorg Med Chem Lett 26:4362-4366 (2016)

PubMed id: 27491711

Optimization of microtubule affinity regulating kinase (MARK) inhibitors with improved physical properties.

D.L.Sloman, N.Noucti, M.D.Altman, D.Chen, A.C.Mislak, A.Szewczak, M.Hayashi, L.Warren, T.Dellovade, Z.Wu, J.Marcus, D.Walker, H.P.Su, S.C.Edavettal, S.Munshi, M.Hutton, H.Nuthall, M.G.Stanton.

ABSTRACT

Inhibition of microtubule affinity regulating kinase (MARK) represents a potentially attractive means of arresting neurofibrillary tangle pathology in Alzheimer's disease. This manuscript outlines efforts to optimize a pyrazolopyrimidine series of MARK inhibitors by focusing on improvements in potency, physical properties and attributes amenable to CNS penetration. A unique cylcyclohexyldiamine scaffold was identified that led to remarkable improvements in potency, opening up opportunities to reduce MW, Pgp efflux and improve pharmacokinetic properties while also conferring improved solubility.