PDBsum entry 4lwc

DNA binding protein/inhibitor

PDB id: 4lwc

Contents

Protein chain

123 a.a.

Ligands

1XU

Waters ×93

PDB id:

4lwc

Name:

DNA binding protein/inhibitor

Title:

Fragment-based discovery of a potent inhibitor of replication protein a protein-protein interactions

Structure:

Replication protein a 70 kda DNA-binding subunit. Chain: a. Fragment: rpa70n (unp residues 1-120). Synonym: rp-a p70, replication factor a protein 1, rf-a protein 1, single-stranded DNA-binding protein, replication protein a 70 kda DNA-binding subunit, n-terminally processed. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: rpa1, repa1, rpa70. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.61Å R-factor: 0.176 R-free: 0.215

Authors:

M.D.Feldkamp,A.O.Frank,J.P.Kennedy,A.G.Waterson,E.O.Olejnczak, N.F.Pelz,J.D.Patrone,B.Vangamudi,D.V.Camper,O.W.Rossanese,S.W.Fesik, W.J.Chazin

Key ref:

A.O.Frank et al. (2013). Discovery of a potent inhibitor of replication protein a protein-protein interactions using a fragment-linking approach. J Med Chem, 56, 9242-9250. PubMed id: 24147804 DOI: 10.1021/jm401333u

Date:

26-Jul-13 Release date: 11-Dec-13

Protein chain

P27694  (RFA1_HUMAN) -  Replication protein A 70 kDa DNA-binding subunit from Homo sapiens

Seq: 616 a.a.

Struc: 123 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

DOI no: 10.1021/jm401333u

J Med Chem 56:9242-9250 (2013)

PubMed id: 24147804

Discovery of a potent inhibitor of replication protein a protein-protein interactions using a fragment-linking approach.

A.O.Frank, M.D.Feldkamp, J.P.Kennedy, A.G.Waterson, N.F.Pelz, J.D.Patrone, B.Vangamudi, D.V.Camper, O.W.Rossanese, W.J.Chazin, S.W.Fesik.

ABSTRACT

Replication protein A (RPA), the major eukaryotic single-stranded DNA (ssDNA)-binding protein, is involved in nearly all cellular DNA transactions. The RPA N-terminal domain (RPA70N) is a recruitment site for proteins involved in DNA-damage response and repair. Selective inhibition of these protein-protein interactions has the potential to inhibit the DNA-damage response and to sensitize cancer cells to DNA-damaging agents without affecting other functions of RPA. To discover a potent, selective inhibitor of the RPA70N protein-protein interactions to test this hypothesis, we used NMR spectroscopy to identify fragment hits that bind to two adjacent sites in the basic cleft of RPA70N. High-resolution X-ray crystal structures of RPA70N-ligand complexes revealed how these fragments bind to RPA and guided the design of linked compounds that simultaneously occupy both sites. We have synthesized linked molecules that bind to RPA70N with submicromolar affinity and minimal disruption of RPA's interaction with ssDNA.