PDBsum entry 4idv

Transferase/transferase inhibitor

PDB id: 4idv

Contents

Protein chains

335 a.a.

Ligands

13V ×4

Waters ×46

PDB id:

4idv

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of nik with compound 4-{3-[2-amino-5-(2- methoxyethoxy)pyrimidin-4-yl]-1h-indol-5-yl}-2-methylbut-3-yn-2-ol (13v)

Structure:

Mitogen-activated protein kinase kinase kinase 14. Chain: a, b, c, d. Fragment: unp residues 330-680. Synonym: nf-kappa-beta-inducing kinase, hsnik, serine/threonine- protein kinase nik. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: map3k14, nik

Resolution:

2.90Å R-factor: 0.207 R-free: 0.269

Authors:

J.Liu,A.Sudom,Z.Wang

Key ref:

K.Li et al. (2013). Inhibiting NF-κB-inducing kinase (NIK): discovery, structure-based design, synthesis, structure-activity relationship, and co-crystal structures. Bioorg Med Chem Lett, 23, 1238-1244. PubMed id: 23374866

Date:

13-Dec-12 Release date: 17-Apr-13

Protein chains

Q99558  (M3K14_HUMAN) -  Mitogen-activated protein kinase kinase kinase 14 from Homo sapiens

Seq: 947 a.a.

Struc: 335 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.11.25 - mitogen-activated protein kinase kinase 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 23:1238-1244 (2013)

PubMed id: 23374866

Inhibiting NF-κB-inducing kinase (NIK): discovery, structure-based design, synthesis, structure-activity relationship, and co-crystal structures.

K.Li, L.R.McGee, B.Fisher, A.Sudom, J.Liu, S.M.Rubenstein, M.K.Anwer, T.D.Cushing, Y.Shin, M.Ayres, F.Lee, J.Eksterowicz, P.Faulder, B.Waszkowycz, O.Plotnikova, E.Farrelly, S.H.Xiao, G.Chen, Z.Wang.

ABSTRACT

The discovery, structure-based design, synthesis, and optimization of NIK inhibitors are described. Our work began with an HTS hit, imidazopyridinyl pyrimidinamine 1. We utilized homology modeling and conformational analysis to optimize the indole scaffold leading to the discovery of novel and potent conformationally constrained inhibitors such as compounds 25 and 28. Compounds 25 and 31 were co-crystallized with NIK kinase domain to provide structural insights.