PDBsum entry 4wwq

Signaling protein

PDB id: 4wwq

Contents

Protein chains

112 a.a.

119 a.a.

Ligands

MLA

Waters ×160

PDB id:

4wwq

Name:

Signaling protein

Title:

Apo structure of the grb7 sh2 domain

Structure:

Growth factor receptor-bound protein 7. Chain: a, b. Fragment: sh2 domain residues 438-555. Synonym: b47,epidermal growth factor receptor grb-7,grb7 adapter protein. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: grb7. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.80Å R-factor: 0.171 R-free: 0.198

Authors:

G.M.Watson,N.D.Ambaye,M.C.Wilce,J.A.Wilce

Key ref:

G.M.Watson et al. (2015). Cyclic Peptides Incorporating Phosphotyrosine Mimetics as Potent and Specific Inhibitors of the Grb7 Breast Cancer Target. J Med Chem, 58, 7707-7718. PubMed id: 26359549 DOI: 10.1021/acs.jmedchem.5b00609

Date:

12-Nov-14 Release date: 23-Sep-15

Protein chain

Q14451  (GRB7_HUMAN) -  Growth factor receptor-bound protein 7 from Homo sapiens

Seq: 532 a.a.

Struc: 112 a.a.

Protein chain

Q14451  (GRB7_HUMAN) -  Growth factor receptor-bound protein 7 from Homo sapiens

Seq: 532 a.a.

Struc: 119 a.a.*

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

DOI no: 10.1021/acs.jmedchem.5b00609

J Med Chem 58:7707-7718 (2015)

PubMed id: 26359549

Cyclic Peptides Incorporating Phosphotyrosine Mimetics as Potent and Specific Inhibitors of the Grb7 Breast Cancer Target.

G.M.Watson, M.J.Gunzburg, N.D.Ambaye, W.A.Lucas, D.A.Traore, K.Kulkarni, K.M.Cergol, R.J.Payne, S.Panjikar, S.C.Pero, P.Perlmutter, M.C.Wilce, J.A.Wilce.

ABSTRACT

The Grb7 adaptor protein is a therapeutic target for both TNBC and HER2+ breast cancer. A nonphosphorylated cyclic peptide 1 (known as G7-18NATE) inhibits Grb7 via targeting the Grb7-SH2 domain, but requires the presence of phosphate ions for both affinity and specificity. Here we report the discovery of malonate bound in the phosphotyrosine binding pocket of the apo-Grb7-SH2 structure. Based on this, we carried out the rational design and synthesis of two analogues of peptide 1 that incorporate carboxymethylphenylalanine (cmF) and carboxyphenylalanine (cF) as mimics of phosphotyrosine (pY). Binding studies using SPR confirmed that affinity for Grb7-SH2 domain is improved up to 9-fold over peptide 1 under physiological phosphate conditions (KD = 2.1-5.7 μM) and that binding is specific for Grb7-SH2 over closely related domains (low or no detectable binding to Grb2-SH2 and Grb10-SH2). X-ray crystallographic structural analysis of the analogue bearing a cmF moiety in complex with Grb7-SH2 has identified the precise contacts conferred by the pY mimic that underpin this improved molecular interaction. Together this study identifies and characterizes the tightest specific inhibitor of Grb7 to date, representing a significant development toward a new Grb7-targeted therapeutic.