 |
PDBsum entry 5e7n
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Protein binding/inhibitor
|
PDB id
|
|
|
|
5e7n
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
PDB id:
|
|
|
|
| Name: |
|
Protein binding/inhibitor
|
|
|
Title:
|
|
Crystal structure of rpa70n in complex with vu0085636
|
|
Structure:
|
|
Replication protein a 70 kda DNA-binding subunit. Chain: a. Fragment: residues 1-120. Synonym: rp-a p70,replication factor a protein 1,rf-a protein 1, single-stranded DNA-binding protein. Engineered: yes. Mutation: yes
|
|
Source:
|
|
Homo sapiens. Human. Organism_taxid: 9606. Gene: rpa1, repa1, rpa70. Expressed in: escherichia coli. Expression_system_taxid: 562.
|
|
Resolution:
|
|
|
1.21Å
|
R-factor:
|
0.197
|
R-free:
|
0.216
|
|
|
Authors:
|
|
B.A.Gilston,J.D.Patrone,N.F.Pelz,B.S.Bates,E.M.Souza-Fagundes, B.Vangamudi,D.Camper,A.Kuznetsov,C.F.Browning,M.D.Feldkamp, E.T.Olejniczak,O.W.Rossanese,A.G.Waterson,S.W.Fesik,W.J.Chazin
|
|
Key ref:
|
|
J.D.Patrone
et al.
(2016).
Identification and Optimization of Anthranilic Acid Based Inhibitors of Replication Protein A.
Chemmedchem,
11,
893-899.
PubMed id:
DOI:
|
|
|
Date:
|
|
|
12-Oct-15
|
Release date:
|
27-Jan-16
|
|
|
|
|
|
|
PROCHECK
|
|
|
|
|
|
Headers
|
|
|
|
References
|
|
|
|
|
|
|
|
P27694
(RFA1_HUMAN) -
Replication protein A 70 kDa DNA-binding subunit from Homo sapiens
|
|
|
|
Seq:
Struc:
|
|
|
|
616 a.a.
123 a.a.*
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Key: |
 |
PfamA domain |
|
|
 |
Secondary structure |
|
 |
CATH domain |
|
|
*
PDB and UniProt seqs differ
at 1 residue position (black
cross)
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
DOI no:
|
Chemmedchem
11:893-899
(2016)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
Identification and Optimization of Anthranilic Acid Based Inhibitors of Replication Protein A.
|
|
J.D.Patrone,
N.F.Pelz,
B.S.Bates,
E.M.Souza-Fagundes,
B.Vangamudi,
D.V.Camper,
A.G.Kuznetsov,
C.F.Browning,
M.D.Feldkamp,
A.O.Frank,
B.A.Gilston,
E.T.Olejniczak,
O.W.Rossanese,
A.G.Waterson,
W.J.Chazin,
S.W.Fesik.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
Replication protein A (RPA) is an essential single-stranded DNA
(ssDNA)-binding protein that initiates the DNA damage response pathway through
protein-protein interactions (PPIs) mediated by its 70N domain. The
identification and use of chemical probes that can specifically disrupt these
interactions is important for validating RPA as a cancer target. A
high-throughput screen (HTS) to identify new chemical entities was conducted,
and 90 hit compounds were identified. From these initial hits, an anthranilic
acid based series was optimized by using a structure-guided iterative medicinal
chemistry approach to yield a cell-penetrant compound that binds to RPA70N with
an affinity of 812 nm. This compound, 2-(3-
(N-(3,4-dichlorophenyl)sulfamoyl)-4-methylbenzamido)benzoic acid (20 c), is
capable of inhibiting PPIs mediated by this domain.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Links
