 |
PDBsum entry 6nss
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Transferase/transferase inhibitor
|
PDB id
|
|
|
|
6nss
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
PDB id:
|
|
|
|
| Name: |
|
Transferase/transferase inhibitor
|
|
|
Title:
|
|
Trk-a in complex with ligand 6
|
|
Structure:
|
|
High affinity nerve growth factor receptor. Chain: a. Fragment: kinase domain. Synonym: neurotrophic tyrosine kinase receptor type 1,trk1- transforming tyrosine kinase protein,tropomyosin-related kinase a, tyrosine kinase receptor,tyrosine kinase receptor a,trk-a,gp140trk, p140-trka. Engineered: yes
|
|
Source:
|
|
Homo sapiens. Human. Organism_taxid: 9606. Gene: ntrk1, mtc, trk, trka. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108
|
|
Resolution:
|
|
|
1.97Å
|
R-factor:
|
0.184
|
R-free:
|
0.218
|
|
|
Authors:
|
|
G.Subramanian,D.G.Brown
|
|
Key ref:
|
|
G.Subramanian
et al.
(2019).
Deciphering the Allosteric Binding Mechanism of the Human Tropomyosin Receptor Kinase A ( hTrkA) Inhibitors.
ACS Chem Biol,
14,
1205-1216.
PubMed id:
DOI:
|
|
|
Date:
|
|
|
25-Jan-19
|
Release date:
|
22-May-19
|
|
|
|
|
|
|
PROCHECK
|
|
|
|
|
|
Headers
|
|
|
|
References
|
|
|
|
|
|
|
|
P04629
(NTRK1_HUMAN) -
High affinity nerve growth factor receptor from Homo sapiens
|
|
|
|
Seq:
Struc:
|
|
|
|
796 a.a.
303 a.a.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Key: |
 |
PfamA domain |
|
|
 |
Secondary structure |
|
|
|
|
|
|
|
|
|
|
|
|
|
Enzyme class:
|
|
E.C.2.7.10.1
- receptor protein-tyrosine kinase.
|
|
|
|
|
|
|
Reaction:
|
|
L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
|
|
|
|
|
|
L-tyrosyl-[protein]
|
+
|
ATP
|
=
|
O-phospho-L-tyrosyl-[protein]
|
+
|
ADP
|
+
|
H(+)
|
|
|
|
|
|
|
|
|
|
|
|
|
Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
|
| |
|
DOI no:
|
ACS Chem Biol
14:1205-1216
(2019)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
Deciphering the Allosteric Binding Mechanism of the Human Tropomyosin Receptor Kinase A ( hTrkA) Inhibitors.
|
|
G.Subramanian,
P.D.Johnson,
T.Zachary,
N.Roush,
Y.Zhu,
S.J.Bowen,
A.Janssen,
B.A.Duclos,
T.Williams,
C.Javens,
N.D.Shalaly,
D.M.Molina,
A.J.Wittwer,
J.L.Hirsch.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
Access to cryptic binding pockets or allosteric sites on a kinase that present
themselves when the enzyme is in a specific conformational state offers a
paradigm shift in designing the next generation small molecule kinase
inhibitors. The current work showcases an extensive and exhaustive array of in
vitro biochemical and biophysical tools and techniques deployed along with
structural biology efforts of inhibitor-bound kinase complexes to characterize
and confirm the cryptic allosteric binding pocket and docking mode of the small
molecule actives identified for hTrkA. Specifically, assays were designed and
implemented to lock the kinase in a predominantly active or inactive
conformation and the effect of the kinase inhibitor probed to understand the
hTrkA binding and hTrkB selectivity. The current outcome suggests that
inhibitors with a fast association rate take advantage of the inactive protein
conformation and lock the kinase state by also exhibiting a slow off-rate. This
in turn shifts the inactive/active state protein conformational equilibrium
cycle, affecting the subsequent downstream signaling.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Links
