FGFR Structural Comparisons

FGFR Structural Comparison:

1CVS, 1DJS, 1E0O, 1EV2, 1FQ9, 1NUN, & 1RY7

Superimposed Upon 1EVT

Larry P. Taylor, Ph. D.

Feedback appreciated; please send comments to:

Email: lpt

Molecular & Behavioral Neuroscience Institute

The University of Michigan

Ann Arbor, MI

The Ligand Binding Domain (LBD, corresponding to Domains D2 and D3 of the FGF Receptors) of FGFR molecules share a similar 3-Dimensional beta sheet sandwich architecture that is characterized by the model compound Telokin. The loops of the LBD are described based on comparisons to this model compound (see Nomenclature). The FGFR crystal structure sequences that were used in the structural comparisons below were aligned using Clustal X. This alignment is shown below:

Tree View, based on the above sequence alignment, provides an evolutionary tree that traces each protein to a common ancestor protein. This graphic is shown below: Since the selected proteins converge to a single hypothetical evolutionary ancestor, these FGF receptor proteins are homologous.

Sequence comparisons can furnish insights into conserved or variable portions of a molecular species, predict some secondary structure characteristics and suggest protein motifs common to known proteins. These tools can provide clues as to areas of the molecule that are biologically interesting. Real molecules, however, do not have gaps in their sequences, so, whenever possible, comparison of 3-D architecture is used to give a better "picture" of molecular behavior. After all, the basic theology of organic chemistry is that form and function are intimately related.

The Calpha backbones of 1CVS, 1DJS, 1E0O, 1EV2, 1FQ9, 1NUN, and 1RY7 were superimposed upon the backbone 1EVT. In addition, selected non-protein material from various crystals were mapped onto the overlays for the purpose of visual orientation. The Calpha only trace for this process is shown in Kinemage 1. The addition of side chains and ribbons for this particular superimposition is shown in Kinemage 3. A subset, FGF 1 bound to FGFR 1, 2c, and 3c, is shown in Kinemage 2. Finally, since the 1E0O overlay appears out of sync a bit (compared to the other ligand-receptor complexes), the backbone overlays minus 1E0O are shown in Kinemage 4.

Perhaps the most obvious observation of these structural overlays is that the linker region between D2 and D3 is highly conserved (the VERSP sequence between ruler count 110 and 120 in the sequences above) in both sequence and three dimensional architecture. The network of hydrogen bonds centered around the invariant Arg residue in this linker region maintains a fairly rigid conformation that presents a consistent ligand binding geometry.

The ligand-D2 interactions (the FGF ligand "high affinity sites") are mostly multiple, disconnected hydrophobic contact points distributed across a reasonably flat surface with a few polar "anchors." The D2 region overlays are less directly superimposed than either the D2-D3 linker or the D3 region. There are abundant non-X-ray resolved regions here that suggest conformational flexibility, even in the bound state.

The FGF ligand "low affinity" (receptor discriminators) interact primarily with the D3 region of the receptor. These contacts are more extensive and possess more of a traditional "lock-and-key" geometry in that a mostly invariant aromatic ring slides into a shallow cavity defined by loop structures in D3 at the lgand-D3 interface. The shape and charges of the "low affinity" loop in the FGF ligand and the loop structures of the D3 region are critical in determining the ultimate binding geometry and overall affinity. Across all FGF receptors, the D3 region is the least conserved, so much of the ligand-receptor discrimination occurs in the D3 domain. The change in these loop structures, especially between 2c and 3c (within the orange box) an be seen in the SYBYL representation of FGF 1 bound to FGFR 1c, 2c and 3c. (the same group as the overlay in Kinemage 2).

The real-time visualization using KiNG of the structures on this site requires a java-enabled (JRE from Java) browser.

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Kinemage 1: Calphas of 1CVS, 1DJS, 1E0O, 1EV2, 1FQ9, 1NUN, and 1RY7 superimposed on 1EVT.

This is just the Calpha backbone "structure browsing" rendering that facilitates a quick download with minimum display.

View 1 The overlay
View 2 The overlay R
View 3 Ligand-D2
View 4 Ligand-D2 R
View 5 Ligand-Linker
View 6 Ligand-Linker R
View 7 Ligand-D3
View 8 Ligand-D3 R

Image requires a Java enabled browser 190 K
Click On KiNG to see	FGFR Backbones

View 1 The overlay
View 2 The overlay R
View 3 Ligand-D2
View 4 Ligand-D2 R
View 5 Ligand-Linker
View 6 Ligand-Linker R
View 7 Ligand-D3
View 8 Ligand-D3 R

Image requires a Java enabled browser 1.23 M
Click On KiNG to see	FGFR Backbones

Kinemage 3: 1CVS, 1DJS, 1E0O, 1EV2, 1FQ9, 1NUN, and 1RY7 superimposed on 1EVT

View 1 The overlay
View 2 The overlay R
View 3 Ligand-D2
View 4 Ligand-D2 R
View 5 Ligand-Linker
View 6 Ligand-Linker R
View 7 Ligand-D3
View 8 Ligand-D3 R

Image requires a Java enabled browser 3.51 M
Click On KiNG to see	FGFR Backbones

Kinemage 4: Calphas of 1CVS, 1DJS, 1EV2, 1FQ9, 1NUN, and 1RY7 superimposed on 1EVT

The structure depicted in 1E0O is unique in that there is a distinctly different ligand-receptor orientation within the dimer unit cell. This could be possibly be a biological control mechanism or an artifact resulting from too much nickel salt in the crystallization solution. In case the 1E0O structure is an artifact, here is the comparison without 1E0O.

View 1 The overlay
View 2 The overlay R
View 3 Ligand-D2
View 4 Ligand-D2 R
View 5 Ligand-Linker
View 6 Ligand-Linker R
View 7 Ligand-D3
View 8 Ligand-D3 R

Image requires a Java enabled browser 2.99 M
Click On KiNG to see	FGFR Backbones

The FGFR protein family constitutes a superb example of conserving a basic three-dimensional geometry with sequence variation to modify biological activity.

The coordinates for the backbones were extracted with SYBYL from Brookhaven Database files coordinate files 1CVS, 1DJS, 1E0O, 1EV2, 1EVT, 1FQ9, 1NUN, and 1RY7 superimposed on 1EVT. Each molecule was separately overlaid on the structure of 1EVT using the "Magic Fit" application of Deep View.