PDBsum entry 6q3c

Cell cycle

PDB id: 6q3c

Contents

Protein chain

289 a.a.

Ligands

BYZ ×2

Waters ×281

PDB id:

6q3c

Name:

Cell cycle

Title:

Cdk2 in complex with fraglite1

Structure:

Cyclin-dependent kinase 2. Chain: a. Synonym: cell division protein kinase 2,p33 protein kinase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: cdk2, cdkn2. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008

Resolution:

1.29Å R-factor: 0.142 R-free: 0.178

Authors:

D.J.Wood,M.P.Martin,M.E.M.Noble

Key ref:

D.J.Wood et al. (2019). FragLites-Minimal, Halogenated Fragments Displaying Pharmacophore Doublets. An Efficient Approach to Druggability Assessment and Hit Generation. J Med Chem, 62, 3741-3752. PubMed id: 30860382 DOI: 10.1021/acs.jmedchem.9b00304

Date:

04-Dec-18 Release date: 20-Mar-19

Protein chain

P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2 from Homo sapiens

Seq: 298 a.a.

Struc: 289 a.a.*

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

Enzyme reactions

• Enzyme class: E.C.2.7.11.22 - cyclin-dependent 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

DOI no: 10.1021/acs.jmedchem.9b00304

J Med Chem 62:3741-3752 (2019)

PubMed id: 30860382

FragLites-Minimal, Halogenated Fragments Displaying Pharmacophore Doublets. An Efficient Approach to Druggability Assessment and Hit Generation.

D.J.Wood, J.D.Lopez-Fernandez, L.E.Knight, I.Al-Khawaldeh, C.Gai, S.Lin, M.P.Martin, D.C.Miller, C.Cano, J.A.Endicott, I.R.Hardcastle, M.E.M.Noble, M.J.Waring.

ABSTRACT

Identifying ligand binding sites on proteins is a critical step in target-based drug discovery. Current approaches to this require resource-intensive screening of large libraries of lead-like or fragment molecules. Here, we describe an efficient and effective experimental approach to mapping interaction sites using a set of halogenated compounds expressing paired hydrogen-bonding motifs, termed FragLites. The FragLites identify productive drug-like interactions, which are identified sensitively and unambiguously by X-ray crystallography, exploiting the anomalous scattering of the halogen substituent. This mapping of protein interaction surfaces provides an assessment of druggability and can identify efficient start points for the de novo design of hit molecules incorporating the interacting motifs. The approach is illustrated by mapping cyclin-dependent kinase 2, which successfully identifies orthosteric and allosteric sites. The hits were rapidly elaborated to develop efficient lead-like molecules. Hence, the approach provides a new method of identifying ligand sites, assessing tractability and discovering new leads.