PDBsum entry 5di1

Transferase/inhibitor

PDB id: 5di1

Contents

Protein chains

285 a.a.

300 a.a.

Ligands

5DF

Waters ×35

PDB id:

5di1

Name:

Transferase/inhibitor

Title:

Map4k4 in complex with an inhibitor

Structure:

Mitogen-activated protein kinase kinase kinase kinase 4. Chain: a, b. Fragment: unp residues 1-310. Synonym: hpk/gck-like kinase hgk,mapk/erk kinase kinase kinase 4, mekkk 4,nck-interacting kinase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: map4k4, hgk, kiaa0687, nik. Expressed in: insect cell expression vector ptie1. Expression_system_taxid: 266783

Resolution:

2.90Å R-factor: 0.200 R-free: 0.249

Authors:

S.Liu

Key ref:

M.Ammirati et al. (2015). Discovery of an in Vivo Tool to Establish Proof-of-Concept for MAP4K4-Based Antidiabetic Treatment. Acs Med Chem Lett, 6, 1128-1133. PubMed id: 26617966 DOI: 10.1021/acsmedchemlett.5b00215

Date:

31-Aug-15 Release date: 13-Jan-16

Protein chain

O95819  (M4K4_HUMAN) -  Mitogen-activated protein kinase kinase kinase kinase 4 from Homo sapiens

Seq: 1239 a.a.

Struc: 285 a.a.

Protein chain

O95819  (M4K4_HUMAN) -  Mitogen-activated protein kinase kinase kinase kinase 4 from Homo sapiens

Seq: 1239 a.a.

Struc: 300 a.a.

Enzyme reactions

• Enzyme class: Chains A, B: 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: 10.1021/acsmedchemlett.5b00215

Acs Med Chem Lett 6:1128-1133 (2015)

PubMed id: 26617966

Discovery of an in Vivo Tool to Establish Proof-of-Concept for MAP4K4-Based Antidiabetic Treatment.

M.Ammirati, S.W.Bagley, S.K.Bhattacharya, L.Buckbinder, A.A.Carlo, R.Conrad, C.Cortes, R.L.Dow, M.S.Dowling, A.El-Kattan, K.Ford, C.R.Guimarães, D.Hepworth, W.Jiao, J.LaPerle, S.Liu, A.Londregan, P.M.Loria, A.M.Mathiowetz, M.Munchhof, S.T.Orr, D.N.Petersen, D.A.Price, A.Skoura, A.C.Smith, J.Wang.

ABSTRACT

Recent studies in adipose tissue, pancreas, muscle, and macrophages suggest that MAP4K4, a serine/threonine protein kinase may be a viable target for antidiabetic drugs. As part of the evaluation of MAP4K4 as a novel antidiabetic target, a tool compound, 16 (PF-6260933) and a lead 17 possessing excellent kinome selectivity and suitable properties were delivered to establish proof of concept in vivo. The medicinal chemistry effort that led to the discovery of these lead compounds is described herein together with in vivo pharmacokinetic properties and activity in a model of insulin resistance.