 |
PDBsum entry 4zk5
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Transferase/transferase inhibitor
|
PDB id
|
|
|
|
4zk5
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
PDB id:
|
|
|
|
| Name: |
|
Transferase/transferase inhibitor
|
|
|
Title:
|
|
Map4k4 in complex with inhibitor gne-495
|
|
Structure:
|
|
Mitogen-activated protein kinase kinase kinase kinase 4. Chain: a, b. Fragment: kinase domain, unp residues 2-238. 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: spodoptera frugiperda. Expression_system_taxid: 7108.
|
|
Resolution:
|
|
|
2.89Å
|
R-factor:
|
0.216
|
R-free:
|
0.265
|
|
|
Authors:
|
|
S.F.Harris,P.Wu,M.Coons
|
|
Key ref:
|
|
C.O.Ndubaku
et al.
(2015).
Structure-Based Design of GNE-495, a Potent and Selective MAP4K4 Inhibitor with Efficacy in Retinal Angiogenesis.
Acs Med Chem Lett,
6,
913-918.
PubMed id:
DOI:
|
|
|
Date:
|
|
|
29-Apr-15
|
Release date:
|
02-Sep-15
|
|
|
|
|
|
|
PROCHECK
|
|
|
|
|
|
Headers
|
|
|
|
References
|
|
|
|
|
|
|
|
O95819
(M4K4_HUMAN) -
Mitogen-activated protein kinase kinase kinase kinase 4 from Homo sapiens
|
|
|
|
Seq:
Struc:
|
|
|
|
1239 a.a.
286 a.a.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Key: |
 |
PfamA domain |
|
|
 |
Secondary structure |
|
 |
CATH domain |
|
|
|
|
|
|
|
|
|
|
|
|
|
Enzyme class:
|
|
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+
|
|
|
|
|
|
|
L-seryl-[protein]
|
+
|
ATP
|
=
|
O-phospho-L-seryl-[protein]
|
+
|
ADP
|
+
|
H(+)
|
|
|
|
|
|
|
L-threonyl-[protein]
|
+
|
ATP
|
=
|
O-phospho-L-threonyl-[protein]
|
+
|
ADP
|
+
|
H(+)
|
|
|
|
|
|
|
|
|
|
|
|
|
Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
|
| |
|
DOI no:
|
Acs Med Chem Lett
6:913-918
(2015)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
Structure-Based Design of GNE-495, a Potent and Selective MAP4K4 Inhibitor with Efficacy in Retinal Angiogenesis.
|
|
C.O.Ndubaku,
T.D.Crawford,
H.Chen,
J.W.Boggs,
J.Drobnick,
S.F.Harris,
R.Jesudason,
E.McNamara,
J.Nonomiya,
A.Sambrone,
S.Schmidt,
T.Smyczek,
P.Vitorino,
L.Wang,
P.Wu,
S.Yeung,
J.Chen,
K.Chen,
C.Z.Ding,
T.Wang,
Z.Xu,
S.E.Gould,
L.J.Murray,
W.Ye.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
Diverse biological roles for mitogen-activated protein kinase kinase kinase
kinase 4 (MAP4K4) have necessitated the identification of potent inhibitors in
order to study its function in various disease contexts. In particular,
compounds that can be used to carry out such studies in vivo would be critical
for elucidating the potential for therapeutic intervention. A structure-based
design effort coupled with property-guided optimization directed at minimizing
the ability of the inhibitors to cross into the CNS led to an advanced compound
13 (GNE-495) that showed excellent potency and good PK and was used to
demonstrate in vivo efficacy in a retinal angiogenesis model recapitulating
effects that were observed in the inducible Map4k4 knockout mice.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Links
