PDBsum entry 5n3e

Transferase

PDB id: 5n3e

Contents

Protein chains

352 a.a.

14 a.a.

Ligands

46L

MPD

DMS

Waters ×248

PDB id:

5n3e

Name:

Transferase

Title:

Camp-dependent protein kinase a from cricetulus griseus in complex with fragment like molecule 6-dimethylaminopyridine-3-carboxylic acid

Structure:

Camp-dependent protein kinase catalytic subunit alpha. Chain: a. Synonym: pka c-alpha. Engineered: yes. Other_details: phosphorylation of s11, s140, t198 and s339. Camp-dependent protein kinase inhibitor. Chain: b. Engineered: yes. Other_details: camp dependent protein kinase inhibitor peptide

Source:

Cricetulus griseus. Chinese hamster. Organism_taxid: 10029. Gene: prkaca. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Expression_system_variant: plyss. Synthetic: yes. Organism_taxid: 10029

Resolution:

1.53Å R-factor: 0.157 R-free: 0.185

Authors:

C.Siefker,A.Heine,G.Klebe

Key ref:

M.Oebbeke et al. (2021). Fragment Binding to Kinase Hinge: If Charge Distribution and Local pK_a Shifts Mislead Popular Bioisosterism Concepts. Angew Chem Int Ed Engl, 60, 252-258. PubMed id: 33021032 DOI: 10.1002/anie.202011295

Date:

08-Feb-17 Release date: 21-Mar-18

Protein chain

P25321  (KAPCA_CRIGR) -  cAMP-dependent protein kinase catalytic subunit alpha from Cricetulus griseus

Seq: 351 a.a.

Struc: 352 a.a.*

Protein chain

G3HK48  (G3HK48_CRIGR) -  cAMP-dependent protein kinase inhibitor alpha from Cricetulus griseus

Seq: 241 a.a.

Struc: 14 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chain A: E.C.2.7.11.11 - cAMP-dependent 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

DOI no: 10.1002/anie.202011295

Angew Chem Int Ed Engl 60:252-258 (2021)

PubMed id: 33021032

Fragment Binding to Kinase Hinge: If Charge Distribution and Local pK_a Shifts Mislead Popular Bioisosterism Concepts.

M.Oebbeke, C.Siefker, B.Wagner, A.Heine, G.Klebe.

ABSTRACT

Medicinal-chemistry optimization follows strategies replacing functional groups and attaching larger substituents at a promising lead scaffold. Well-established bioisosterism rules are considered, however, it is difficult to estimate whether the introduced modifications really match the required properties at a binding site. The electron density distribution and pK_a values are modulated influencing protonation states and bioavailability. Considering the adjacent H-bond donor/acceptor pattern of the hinge binding motif in a kinase, we studied by crystallography a set of fragments to map the required interaction pattern. Unexpectedly, benzoic acid and benzamidine, decorated with the correct substituents, are totally bioisosteric just as carboxamide and phenolic OH. A mono-dentate pyridine nitrogen out-performs bi-dentate functionalities. The importance of correctly designing pK_a values of attached functional groups by additional substituents at the parent scaffold is rendered prominent.