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PDBsum entry 1gq5
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Signaling protein
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PDB id
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1gq5
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Structural determinants of the na+/h+ exchanger regulatory factor interaction with the beta 2 adrenergic and platelet-Derived growth factor receptors.
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Authors
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S.Karthikeyan,
T.Leung,
J.A.Ladias.
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Ref.
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J Biol Chem, 2002,
277,
18973-18978.
[DOI no: ]
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PubMed id
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Abstract
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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.
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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).
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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.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2002,
277,
18973-18978)
copyright 2002.
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Secondary reference #1
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Title
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Structural basis of the na+/h+ exchanger regulatory factor pdz1 interaction with the carboxyl-Terminal region of the cystic fibrosis transmembrane conductance regulator.
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Authors
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S.Karthikeyan,
T.Leung,
J.A.Ladias.
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Ref.
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J Biol Chem, 2001,
276,
19683-19686.
[DOI no: ]
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PubMed id
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Figure 1.
Fig. 1. Structure of the NHERF PDZ1 domain bound to the
CFTR sequence QDTRL. A, sequence comparison of PDZ domains that
bind to CFTR. The indicated PDZ domains from human NHERF (5),
human NHERF2 (8), and murine PDZK1/CAP70 (12) were aligned using
MACAW (36). Absolutely conserved residues are shown as white
letters on blue background. Identical residues in four domains
are shaded in cyan. The secondary structure of NHERF PDZ1 is
indicated at the top. Conserved acidic residues proposed to
interact with Arg 1 of the
CFTR ligand are denoted by an asterisk. B, stereo view of the
NHERF PDZ1 crystal packing. Each carboxyl terminus serves as a
ligand for a neighboring PDZ1 molecule. C, ribbon diagram of the
NHERF PDZ1 domain bound to the QDTRL peptide. The strands 1- 6 are shown
in yellow, and the helices 1 and 2 are shown
in green. The peptide ligand QDTRL is shown in pink. The figure
was made using MOLSCRIPT (37) and Raster3D (38). D, surface
topology of the NHERF PDZ1 bound to the peptide QDTRL. The
figure was generated using GRASP (39).
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Figure 2.
Fig. 2. NHERF PDZ1 interactions with the peptide QDTRL.
A, stereo view of a 2F[obs] F[calc]
electron density map calculated at 1.7-Å resolution and
contoured at 1 at the
peptide-binding site. B, stereo image of the NHERF PDZ1 binding
pocket bound to the carboxyl-terminal peptide ligand (gray).
Carbon, oxygen, and nitrogen atoms are shown in black, red, and
blue, respectively. Water molecules are shown as red spheres and
hydrogen bonds as dashed lines. C, two-dimensional
representation of the interactions observed between the NHERF
PDZ1 residues (orange) and the peptide ligand (purple). Dashed
lines denote hydrogen bonds, and numbers indicate hydrogen bond
lengths in Å. Hydrophobic interactions are shown as arcs
with radial spokes. The figure was made using LIGPLOT (40).
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The above figures are
reproduced from the cited reference
with permission from the ASBMB
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Secondary reference #2
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Title
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Crystal structure of the pdz1 domain of human na(+)/h(+) exchanger regulatory factor provides insights into the mechanism of carboxyl-Terminal leucine recognition by class i pdz domains.
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Authors
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S.Karthikeyan,
T.Leung,
G.Birrane,
G.Webster,
J.A.Ladias.
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Ref.
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J Mol Biol, 2001,
308,
963-973.
[DOI no: ]
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PubMed id
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Figure 7.
Figure 7. Two-dimensional schematic representation of the
contacts observed in the NHERF PDZ1 binding pocket. PDZ1
residues (orange) making hydrogen bonds and hydrophobic contacts
with the peptide ligand (purple) are shown in ball-and-stick
representation. Carbon atoms are shown in white, oxygen atoms in
red, and nitrogen atoms in blue. Water molecules are shown as
green spheres. Hydrogen bonds are depicted as broken lines and
numbers indicate distances in Å. Val76 involved in
hydrophobic interaction with the C^d2 atom of Leu0 is shown as
an arc with radial spokes. The Figure was generated using the
program LIGPLOT[49].
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Figure 8.
Figure 8. Carboxyl-terminal leucine and valine recognition
by PDZ domains. Surface representation of the hydrophobic
pockets of (a) human NHERF PDZ1 and (b) rat PSD-95 PDZ3 bound to
carboxyl-terminal leucine and valine residues, respectively. The
limits of the hydrophobic cavities are denoted with jagged
edges. The Figure was made with the program GRASP[50].
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The above figures are
reproduced from the cited reference
with permission from Elsevier
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