PDBsum entry 4x2k

Transferase

PDB id: 4x2k

Contents

Protein chain

303 a.a.

Ligands

3WO

SO4

Waters ×250

PDB id:

4x2k

Name:

Transferase

Title:

Selection of fragments for kinase inhibitor design: decoration is key

Structure:

Tgf-beta receptor type-1. Chain: a. Synonym: tgfr-1,activin a receptor type ii-like protein kinase of 53kd,activin receptor-like kinase 5,alk5,serine/threonine-protein kinase receptor r4,skr4,tgf-beta type i receptor,transforming growth factor-beta receptor type i,tbetar-i. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: tgfbr1, alk5, skr4. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

1.69Å R-factor: 0.167 R-free: 0.184

Authors:

P.Czodrowski,G.Hoelzemann,G.Barnickel,H.Greiner,D.Musil

Key ref:

P.Czodrowski et al. (2015). Selection of fragments for kinase inhibitor design: decoration is key. J Med Chem, 58, 457-465. PubMed id: 25437144 DOI: 10.1021/jm501597j

Date:

26-Nov-14 Release date: 24-Dec-14

Protein chain

P36897  (TGFR1_HUMAN) -  TGF-beta receptor type-1 from Homo sapiens

Seq: 503 a.a.

Struc: 303 a.a.*

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

Enzyme reactions

• Enzyme class: E.C.2.7.11.30 - receptor protein serine/threonine kinase.
• Reaction:
  1. L-seryl-[receptor-protein] + ATP = O-phospho-L-seryl-[receptor- protein] + ADP + H⁺
  2. L-threonyl-[receptor-protein] + ATP = O-phospho-L-threonyl-[receptor- protein] + ADP + H⁺

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

reference

DOI no: 10.1021/jm501597j

J Med Chem 58:457-465 (2015)

PubMed id: 25437144

Selection of fragments for kinase inhibitor design: decoration is key.

P.Czodrowski, G.Hölzemann, G.Barnickel, H.Greiner, D.Musil.

ABSTRACT

In fragment-based screening, the choice of the best suited fragment hit among the detected hits is crucial for success. In our study, a kinase lead compound was fragmented, the hinge-binding motif extracted as a core fragment, and a minilibrary of five similar compounds with fragment-like properties was selected from our proprietary compound database. The structures of five fragments in complex with transforming growth factor β receptor type 1 kinase domain were determined by X-ray crystallography. Three different binding modes of the fragments are observed that depend on the position and the type of the substitution at the core fragment. The influence of different substituents on the preferred fragment pose was analyzed by various computational approaches. We postulate that the replacement of water molecules leads to the different binding modes.