PDBsum entry 2aoa

Transferase

PDB id: 2aoa

Contents

Protein chains

93 a.a. *

77 a.a. *

Ligands

S1S ×3

P33

Waters ×103

* Residue conservation analysis

PDB id:

2aoa

Name:

Transferase

Title:

Crystal structures of a high-affinity macrocyclic peptide mimetic in complex with the grb2 sh2 domain

Structure:

Growth factor receptor-bound protein 2. Chain: a, b. Fragment: sh2 (residues 55 - 153). Synonym: grb2 adapter protein, sh2/sh3 adapter grb2, ash protein. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: grb2, ash. Expressed in: escherichia coli. Expression_system_taxid: 562

Biol. unit:

Dimer (from PQS)

Resolution:

1.99Å R-factor: 0.249 R-free: 0.307

Authors:

J.Phan,Z.D.Shi,T.R.Burke,D.S.Waugh

Key ref:

J.Phan et al. (2005). Crystal structures of a high-affinity macrocyclic peptide mimetic in complex with the Grb2 SH2 domain. J Mol Biol, 353, 104-115. PubMed id: 16165154 DOI: 10.1016/j.jmb.2005.08.037

Date:

12-Aug-05 Release date: 04-Oct-05

Protein chain

P62993  (GRB2_HUMAN) -  Growth factor receptor-bound protein 2 from Homo sapiens

Seq: 217 a.a.

Struc: 93 a.a.

Protein chain

P62993  (GRB2_HUMAN) -  Growth factor receptor-bound protein 2 from Homo sapiens

Seq: 217 a.a.

Struc: 77 a.a.

Enzyme reactions

• Enzyme class: Chains A, B: E.C.?

DOI no: 10.1016/j.jmb.2005.08.037

J Mol Biol 353:104-115 (2005)

PubMed id: 16165154

Crystal structures of a high-affinity macrocyclic peptide mimetic in complex with the Grb2 SH2 domain.

J.Phan, Z.D.Shi, T.R.Burke, D.S.Waugh.

ABSTRACT

The high-affinity binding of the growth factor receptor-bound protein 2 (Grb2) SH2 domain to tyrosine-phosphorylated cytosolic domains of receptor tyrosine kinases (RTKs) is an attractive target for therapeutic intervention in many types of cancer. We report here two crystal forms of a complex between the Grb2 SH2 domain and a potent non-phosphorus-containing macrocyclic peptide mimetic that exhibits significant anti-proliferative effects against erbB-2-dependent breast cancers. This agent represents a "second generation" inhibitor with greatly improved binding affinity and bio-availability compared to its open-chain counterpart. The structures were determined at 2.0A and 1.8A with one and two domain-swapped dimers per asymmetric unit, respectively. The mode of binding and specific interactions between the protein and the inhibitor provide insight into the high potency of this class of macrocylic compounds and may aid in further optimization as part of the iterative rational drug design process.

Selected figure(s)

Figure 3.
Figure 3. Diagrams of the hydrogen bonding networks in the active site of (a) subunit A and (b) subunit B with the Grb2 SH2 domain represented in cartoon, ligand-binding residues in bonds with grey carbon atoms, and ligands in ball-and-stick with green carbon atoms. Hydrogen bonds are in cyan broken lines and intramolecular bonds in red. Selected atoms of S1s are labeled in red.

Figure 4.
Figure 4. (a) Binding interactions between two S1s molecules and the Grb2 SH2 domain in the C site, green and orange, and D site, cyan and yellow ball-and-stick models. (b) Stereo view of the superposition of Grb2 SH2 ligands from PDB entries 1ZFP (magenta), 1FYR (gold), 1BM2 (cyan), 1TZE (slate blue), and 1CJ1 (tomato) on subunit A S1s (green). The carbon atoms of the S1s-binding residues in ball-and-stick are grey and the ligands are in bonds. Hydrogen bonds are shown in red broken lines for S1s. Superposition of all 12 S1s molecules in stereo showing different side-chain rotamers and conformational changes derived from binding in the various pockets of the domain-swapped dimer. (c) Those that bound in the A site are in black, B site in dark green, C site in orange and red, and D site in blue and cyan.

The above figures are reprinted by permission from Elsevier: J Mol Biol (2005, 353, 104-115) copyright 2005.

Figures were selected by an automated process.