PDBsum entry 3ndm

Transferase/transferase inhibitor

PDB id: 3ndm

Contents

Protein chain

383 a.a. *

Ligands

3ND ×3

Waters ×65

* Residue conservation analysis

PDB id:

3ndm

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of rho-associated protein kinase (rock1) with a potent isoquinolone derivative

Structure:

Rho-associated protein kinase (rock1). Chain: a, b, c, d. Fragment: n-terminal and kinase domain, residues 6-415. Synonym: rock1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Resolution:

3.30Å R-factor: 0.244 R-free: 0.311

Authors:

X.Li

Key ref:

T.Bosanac et al. (2010). Substituted 2H-isoquinolin-1-ones as potent Rho-kinase inhibitors: part 3, aryl substituted pyrrolidines. Bioorg Med Chem Lett, 20, 3746-3749. PubMed id: 20471253

Date:

07-Jun-10 Release date: 08-Dec-10

Protein chains

Q13464  (ROCK1_HUMAN) -  Rho-associated protein kinase 1 from Homo sapiens

Seq: 1354 a.a.

Struc: 383 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: 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⁺

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

reference

Bioorg Med Chem Lett 20:3746-3749 (2010)

PubMed id: 20471253

Substituted 2H-isoquinolin-1-ones as potent Rho-kinase inhibitors: part 3, aryl substituted pyrrolidines.

T.Bosanac, E.R.Hickey, J.Ginn, M.Kashem, S.Kerr, S.Kugler, X.Li, A.Olague, S.Schlyer, E.R.Young.

ABSTRACT

The discovery and SAR of a series of beta-aryl substituted pyrrolidine 2H-isoquinolin-1-one inhibitors of Rho-kinase (ROCK) derived from 2 is herein described. SAR studies have shown that aryl groups in the beta-position are optimal for potency. Our efforts focused on improving the ROCK potency of this isoquinolone class of inhibitors which led to the identification of pyrrolidine 32 which demonstrated a 10-fold improvement in aortic ring (AR) potency over 2.