PDBsum entry 1gq5

Signaling protein

PDB id: 1gq5

Contents

Protein chain

91 a.a. *

Metals

_CL ×2

Waters ×55

* Residue conservation analysis

PDB id:

1gq5

Name:

Signaling protein

Title:

Structural determinants of the nherf interaction with beta2-ar and pdgfr

Structure:

Ezrin-radixin-moesin binding phosphoprotein-50. Chain: a. Fragment: pdz1 domain, residues 11-94. Synonym: na+/h+ exchanger regulatory factor. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.20Å R-factor: 0.225 R-free: 0.263

Authors:

S.Karthikeyan,T.Leung,J.A.A.Ladias

Key ref:

S.Karthikeyan et al. (2002). Structural determinants of the Na+/H+ exchanger regulatory factor interaction with the beta 2 adrenergic and platelet-derived growth factor receptors. J Biol Chem, 277, 18973-18978. PubMed id: 11882663 DOI: 10.1074/jbc.M201507200

Date:

20-Nov-01 Release date: 14-Nov-02

Protein chain

O14745  (NHRF1_HUMAN) -  Na(+)/H(+) exchange regulatory cofactor NHE-RF1 from Homo sapiens

Seq: 358 a.a.

Struc: 91 a.a.*

* PDB and UniProt seqs differ at 5 residue positions (black crosses)

DOI no: 10.1074/jbc.M201507200

J Biol Chem 277:18973-18978 (2002)

PubMed id: 11882663

Structural determinants of the Na+/H+ exchanger regulatory factor interaction with the beta 2 adrenergic and platelet-derived growth factor receptors.

S.Karthikeyan, T.Leung, J.A.Ladias.

ABSTRACT

The Na(+)/H(+) exchanger regulatory factor (NHERF) binds through its PDZ1 domain to the carboxyl-terminal sequences NDSLL and EDSFL of the beta(2) adrenergic receptor (beta(2)AR) and platelet-derived growth factor receptor, respectively, and plays a critical role in the membrane localization and physiological regulation of these receptors. The crystal structures of the human NHERF PDZ1 domain bound to the sequences NDSLL and EDSFL have been determined at 1.9- and 2.2-A resolution, respectively. The beta(2)AR and platelet-derived growth factor receptor ligands insert into the PDZ1 binding pocket by a beta-sheet augmentation process and are stabilized by largely similar networks of hydrogen bonds and hydrophobic contacts. In the PDZ1-beta(2)AR complex, the side chain of asparagine at position -4 in the beta(2)AR peptide forms two additional hydrogen bonds with Gly(30) of PDZ1, which contribute to the higher affinity of this interaction. Remarkably, both complexes are further stabilized by hydrophobic interactions involving the side chains of the penultimate amino acids of the peptide ligands, whereas the PDZ1 residues Asn(22) and Glu(43) undergo conformational changes to accommodate these side chains. These results provide structural insights into the mechanisms by which different side chains at the position -1 of peptide ligands interact with PDZ domains and contribute to the affinity of the PDZ-ligand interaction.

Selected figure(s)

Figure 1.
Fig. 1. Structure of the hNHERF PDZ1 domain bound to the [2]AR and PDGFR carboxyl-terminal sequences. A, sequences of the chimeric hNHERF PDZ1- [2]AR (PDZ1B) and PDZ1-PDGFR (PDZ1P) proteins used in this study. Amino acid residues belonging to the [2]AR and PDGFR carboxyl termini are shaded in yellow. Secondary structure elements are indicated at the top. B, stereo view of the hNHERF PDZ1- [2]AR crystal packing. Each carboxyl terminus serves as a ligand for a neighboring PDZ1 molecule. C, ribbon diagram of the hNHERF PDZ1 domain bound to the [2]AR carboxyl-terminal sequence NDSLL. A weighted 2F[obs] F[calc] electron density map calculated at 1.9-Å resolution and contoured at 1.0 is superimposed on the [2]AR ligand. D, ribbon diagram of the hNHERF PDZ1 domain bound to the PDGFR carboxyl-terminal sequence EDSFL. A weighted 2F[obs] F[calc] electron density map calculated at 2.2-Å resolution and contoured at 1.0 is superimposed on the PDGFR ligand. The figure was made using MOLSCRIPT (35), BOBSCRIPT (36), Raster3D (37), and POV-Ray (www.povray.org).

Figure 2.
Fig. 2. PDZ1 interaction with the [2]AR and PDGFR carboxyl termini. A and B, stereo images of the hNHERF PDZ1 binding pocket bound to the [2]AR (A) and PDGFR (B) carboxyl-terminal ligands. Carbon, oxygen, and nitrogen atoms are shown in black, red, and blue, respectively. Water molecules are depicted as green spheres, and hydrogen bonds are shown as dashed lines. C and D, two-dimensional representations of the interactions observed between the hNHERF PDZ1 residues (orange) and [2]AR (C) or PDGFR (D) peptide ligands (purple). Dashed lines denote hydrogen bonds, and numbers indicate hydrogen bond lengths in Å. Hydrophobic interactions are shown as arcs with radial spokes. C and D were generated using LIGPLOT (38). E, superposition of the hNHERF PDZ1 bound to CFTR (yellow), [2]AR (blue), and PDGFR (pink) peptide ligands. For clarity, the 2 strand and 2 helix of the PDZ1 domain are shown as ribbon diagrams, and only the C^ traces are shown for the remaining PDZ1 main chain. Side chains of the peptide ligands and the PDZ1 residues Asn22 and Glu43 are shown as ball-and-stick models.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2002, 277, 18973-18978) copyright 2002.