 |
PDBsum entry 3sx0
|
|
|
|
PDB id:
|
|
|
|
| Name: |
|
Transferase
|
|
|
Title:
|
|
Crystal structure of dot1l in complex with a brominated sah analog
|
|
Structure:
|
|
Histone-lysine n-methyltransferase, h3 lysine-79 specific. Chain: a. Fragment: sequence database residues 1-420. Synonym: dot1-like protein, histone h3-k79 methyltransferase, h3-k79- hmtase, lysine n-methyltransferase 4. Engineered: yes
|
|
Source:
|
|
Homo sapiens. Human. Organism_taxid: 9606. Gene: dot1l, kiaa1814, kmt4. Expressed in: escherichia coli. Expression_system_taxid: 511693.
|
|
Resolution:
|
|
|
2.28Å
|
R-factor:
|
0.210
|
R-free:
|
0.228
|
|
|
Authors:
|
|
W.Yu,W.Tempel,D.Smil,M.Schapira,Y.Li,M.Vedadi,K.T.Nguyen, A.K.Wernimont,C.H.Arrowsmith,A.M.Edwards,C.Bountra,J.Weigelt, P.J.Brown,Structural Genomics Consortium (Sgc)
|
|
Key ref:
|
|
W.Yu
et al.
(2013).
Bromo-deaza-SAH: a potent and selective DOT1L inhibitor.
Bioorg Med Chem,
21,
1787-1794.
PubMed id:
|
|
|
Date:
|
|
|
14-Jul-11
|
Release date:
|
27-Jul-11
|
|
|
|
|
|
|
PROCHECK
|
|
|
|
|
|
Headers
|
|
|
|
References
|
|
|
|
|
|
|
|
Q8TEK3
(DOT1L_HUMAN) -
Histone-lysine N-methyltransferase, H3 lysine-79 specific from Homo sapiens
|
|
|
|
Seq:
Struc:
|
|
|
|
1537 a.a.
324 a.a.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Key: |
 |
PfamA domain |
|
|
 |
Secondary structure |
|
 |
CATH domain |
|
|
|
|
|
|
|
|
|
|
|
|
|
Enzyme class:
|
|
E.C.2.1.1.360
- [histone H3]-lysine(79) N-trimethyltransferase.
|
|
|
|
|
|
|
Reaction:
|
|
L-lysyl79-[histone H3] + 3 S-adenosyl-L-methionine = N6,N6,N6- trimethyl-L-lysyl79-[histone H3] + 3 S-adenosyl-L-homocysteine + 3 H+
|
|
|
|
|
|
L-lysyl(79)-[histone H3]
|
+
|
3
×
S-adenosyl-L-methionine
|
=
|
N(6),N(6),N(6)- trimethyl-L-lysyl(79)-[histone H3]
|
+
|
3
×
S-adenosyl-L-homocysteine
|
+
|
3
×
H(+)
Bound ligand (Het Group name = )
matches with 89.29% similarity
|
|
|
|
|
|
|
|
|
|
|
|
|
Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
|
| |
|
|
Bioorg Med Chem
21:1787-1794
(2013)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
Bromo-deaza-SAH: a potent and selective DOT1L inhibitor.
|
|
W.Yu,
D.Smil,
F.Li,
W.Tempel,
O.Fedorov,
K.T.Nguyen,
Y.Bolshan,
R.Al-Awar,
S.Knapp,
C.H.Arrowsmith,
M.Vedadi,
P.J.Brown,
M.Schapira.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
Chemical inhibition of proteins involved in chromatin-mediated signaling is an
emerging strategy to control chromatin compaction with the aim to reprogram
expression networks to alter disease states. Protein methyltransferases
constitute one of the protein families that participate in epigenetic control of
gene expression, and represent a novel therapeutic target class. Recruitment of
the protein lysine methyltransferase DOT1L at aberrant loci is a frequent
mechanism driving acute lymphoid and myeloid leukemias, particularly in infants,
and pharmacological inhibition of DOT1L extends survival in a mouse model of
mixed lineage leukemia. A better understanding of the structural chemistry of
DOT1L inhibition would accelerate the development of improved compounds. Here,
we report that the addition of a single halogen atom at a critical position in
the cofactor product S-adenosylhomocysteine (SAH, an inhibitor of SAM-dependent
methyltransferases) results in an 8-fold increase in potency against DOT1L, and
reduced activities against other protein and non-protein methyltransferases. We
solved the crystal structure of DOT1L in complex with Bromo-deaza-SAH and
rationalized the observed effects. This discovery reveals a simple strategy to
engineer selectivity and potency towards DOT1L into the adenosine scaffold of
the cofactor shared by all methyltransferases, and can be exploited towards the
development of clinical candidates against mixed lineage leukemia.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Links
