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PDBsum entry 4lwt
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Ligase/ligase inhibitor
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PDB id
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4lwt
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PDB id:
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| Name: |
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Ligase/ligase inhibitor
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Title:
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The 1.6a crystal structure of humanized xenopus mdm2 with ro5027344
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Structure:
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E3 ubiquitin-protein ligase mdm2. Chain: a. Fragment: n-terminal domain (unp residues 21-105). Synonym: double minute 2 protein, xdm2, p53-binding protein mdm2. Engineered: yes. Mutation: yes
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Source:
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Xenopus laevis. Clawed frog,common platanna,platanna. Organism_taxid: 8355. Gene: mdm2. Expressed in: escherichia coli. Expression_system_taxid: 511693.
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Resolution:
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1.60Å
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R-factor:
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0.223
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R-free:
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0.247
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Authors:
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B.J.Graves,C.Lukacs,U.Kammlott
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Key ref:
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Z.Zhang
et al.
(2014).
Discovery of potent and selective spiroindolinone MDM2 inhibitor, RO8994, for cancer therapy.
Bioorg Med Chem Lett,
22,
4001-4009.
PubMed id:
DOI:
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Date:
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28-Jul-13
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Release date:
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16-Jul-14
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PROCHECK
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Headers
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References
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P56273
(MDM2_XENLA) -
E3 ubiquitin-protein ligase Mdm2 from Xenopus laevis
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Seq:
Struc:
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473 a.a.
86 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 4 residue positions (black
crosses)
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Enzyme class:
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E.C.2.3.2.27
- RING-type E3 ubiquitin transferase.
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Reaction:
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S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N6- ubiquitinyl-[acceptor protein]-L-lysine
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DOI no:
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Bioorg Med Chem Lett
22:4001-4009
(2014)
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PubMed id:
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Discovery of potent and selective spiroindolinone MDM2 inhibitor, RO8994, for cancer therapy.
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Z.Zhang,
Q.Ding,
J.J.Liu,
J.Zhang,
N.Jiang,
X.J.Chu,
D.Bartkovitz,
K.C.Luk,
C.Janson,
C.Tovar,
Z.M.Filipovic,
B.Higgins,
K.Glenn,
K.Packman,
L.T.Vassilev,
B.Graves.
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ABSTRACT
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The field of small-molecule inhibitors of protein-protein interactions is
rapidly advancing and the specific area of inhibitors of the p53/MDM2
interaction is a prime example. Several groups have published on this topic and
multiple compounds are in various stages of clinical development. Building on
the strength of the discovery of RG7112, a Nutlin imidazoline-based compound,
and RG7388, a pyrrolidine-based compound, we have developed additional scaffolds
that provide opportunities for future development. Here, we report the discovery
and optimization of a highly potent and selective series of spiroindolinone
small-molecule MDM2 inhibitors, culminating in RO8994.
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Links
