PDBsum entry 4x7q

Transferase/transferase inhibitor

PDB id: 4x7q

Contents

Protein chains

243 a.a.

217 a.a.

Ligands

3YR ×2

PO4

Waters ×77

PDB id:

4x7q

Name:

Transferase/transferase inhibitor

Title:

Pim2 kinase in complex with compound 1s

Structure:

Serine/threonine-protein kinase pim-2. Chain: b, a. Fragment: pim2 kinase. Synonym: pim-2h. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pim2. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.33Å R-factor: 0.199 R-free: 0.258

Authors:

D.J.Marcotte,L.F.Silvian

Key ref:

A.Ishchenko et al. (2015). Structure-based design of low-nanomolar PIM kinase inhibitors. Bioorg Med Chem Lett, 25, 474-480. PubMed id: 25575657 DOI: 10.1016/j.bmcl.2014.12.041

Date:

09-Dec-14 Release date: 11-Feb-15

Protein chain

Q9P1W9  (PIM2_HUMAN) -  Serine/threonine-protein kinase pim-2 from Homo sapiens

Seq: 311 a.a.

Struc: 243 a.a.

Protein chain

Q9P1W9  (PIM2_HUMAN) -  Serine/threonine-protein kinase pim-2 from Homo sapiens

Seq: 311 a.a.

Struc: 217 a.a.

Enzyme reactions

• Enzyme class: Chains B, A: 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

DOI no: 10.1016/j.bmcl.2014.12.041

Bioorg Med Chem Lett 25:474-480 (2015)

PubMed id: 25575657

Structure-based design of low-nanomolar PIM kinase inhibitors.

A.Ishchenko, L.Zhang, J.Y.Le Brazidec, J.Fan, J.H.Chong, A.Hingway, A.Raditsis, L.Singh, B.Elenbaas, V.S.Hong, D.Marcotte, L.Silvian, I.Enyedy, J.Chao.

ABSTRACT

PIM kinases are implicated in variety of cancers by promoting cell survival and proliferation and are targets of interest for therapeutic intervention. We have identified a low-nanomolar pan-PIM inhibitor (PIM1/2/3 potency 5:14:2nM) using structure based modeling. The crystal structure of this compound with PIM1 confirmed the predicted binding mode and protein-ligand interactions except those in the acidic ribose pocket. We show the SAR suggesting the importance of having a hydrogen bond donor in this pocket for inhibiting PIM2; however, this interaction is not important for inhibiting PIM1 or PIM3. In addition, we report the discovery of a new class of PIM inhibitors by using computational de novo design tool implemented in MOE software (Chemical Computing Group). These inhibitors have a different interaction profile.