Human FGF 1 Bound To FGFR 1c

by

Larry P. Taylor, Ph. D.

 

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Email: lpt

Molecular & Behavioral Neuroscience Institute

The University of Michigan

Ann Arbor, MI

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FGF Site: FGF Intro     Nomenclature     Notes      References     FGF Sequences     FGFR Sequences  

Human Fibroblast Growth Factor  1 Bound To FGF Receptor 1c

The unit cell for the FGF 1-FGFR 1c dimer complex is shown in Kinemage 1. Kinemage 2 adds main chains, main chain H-bonding, side chains, and ribbon rendering to the unit cell of Kinemage 1. Kinemage 3 is the secondary structure cartoon for the complex. There are two ordered sulfate ions near the region of the FGF ligand associated with FGF-heparin binding. The kinemages also shows the highly conserved disulphide bonds in FGFR 1 domains D2 and D3. The characteristics of the unit cell for this structure are summarized at pdbsum.

Comparison (Kinemage 4) of FGF 1 in both the free (from Brookhaven file 1AXM) and FGFR 1 receptor-bound states suggests a few areas of difference that may or may not be of biological significance. The areas of divergence are centered around Glu-91, Glu-104, and His-124.

Distance Measurements (in Angstroms) between selected bound and unbound side chains:

Glu 90 (side chain delta carbon) = 4.81
Glu-91 (side chain delta carbon) = 3.08
His-93 (side chain epsilon nitrogen) = 2.11

Glu-104 (side chain delta carbon) = 2.41
Asn-106 (side chain gamma carbon) = 1.92

His-124 (side chain epsilon nitrogen) = 2.84

The ligand binding domain of the FGF Receptors is found in the highly conserved immunoglobulin-like regions of the second (D2) and third (D3) domains of the receptor sequence. The primary binding site of the receptor (with the ligand high affinity region) is the highly conserved portion of the D2 domain and the linker between the D2 and D3 FGF receptor domains. Ligand specificity is acquired via sequence variability and alternative splicing of the receptor that leads to a highly variable realm within 2 loops of the D3 region of the FGF receptor that interacts with the N-terminal and low-affinity loop portions of the FGF ligand. (The D3 Domain is assembled from three exons termed a, b and c.)

The interactions between FGF 1 and the D2 region of FGFR 1c (Kinemage 5) are primarily hydrophobic. These involve FGF 1 residues Tyr-15, Phe-17, Gly-19, Gly-20, Phe-22, His-93, Tyr-94, Leu-133, Leu-135, and Pro-136. The FGFR 1c residues involved are primarily along the beta stand containing the aliphatic portion of Lys-163, Leu-165, Ala-167, and Pro-169 with additional hydrophobicity contributed by Val-248. The primary points of interaction are a strong hydrophobic center defined by Tyr-15, Leu-133, and Leu-135 of FGF 1 surrounding the Ala-167 of FGFR 1.

These ligand-receptor interactions at the D2 domain of the receptor are strengthened by hydrogen bonding between the FGF ligand Ser-17 backbone carbonyl and the side chain amino group of receptor Lys-183 and another hydrogen bond between the oxygen of the phenol group of ligand Tyr-15 and the backbone NH moiety of receptor Ala-167.

Another hydrophobic center of interaction occurs between the ligand FGF 1 and the linker region (Kinemage 6) between D2 and D3 of FGFR 1c. These hydrophobic interactions provide a distinctly non-polar local environment which increases any possible electronic interactions. The ligand residues Leu-89 and Pro-136 coupled with receptor residues Val-248 and Pro-252 provide a hydrophobic cavity surrounding the invariant polar residue, Arg-250.

So, the hydrogen bond in this region between the invariant Arg-251 of the FGFR 1c receptor with the side chain of Asn-95 of the FGF 1 ligand is particularly important. 

A network of intra-chain hydrogen bonding in both ligand and receptor adds conformational stabilization to the ligand binding in the receptor D2-D3 linker region. This network of hydrogen bonds, especially between Arg-251 and invariant Asp-282 of the receptor and between Asn-95 and Tyr-97 (which also H-bonds to ligand residue Glu-87) of the ligand could serve as a barrier to rotation about the critical Arg-250 residue of the receptor. A restriction of rotation here would facilitate ligand-receptor interactions.

Since there is much sequence variation (primarily as a result of splice variation) in the loop regions of  FGF receptor domain D3, the D3 domain of FGF receptors is associated with ligand discrimination. This region is associated with the low affinity loop (defined by the turn between beta loops 8 and 9 of the FGF trefoil structure) of FGF molecules. This interaction is shown in Kinemage 7.

Hydrophobic interactions primarily involve a cavity defined by FGFR 1 residues Val-279, Pro-285, and Ile-287. This cavity, upon FGF 1 binding, is occupied by FGF 1 residue Tyr-8.

Hydrogen bonding stabilization of FGF ligand to receptor binding in the D3 Domain include the phenol group of Tyr-8 to the backbone carbonyl of receptor residue Pro-285, side chain of ligand residue Glu-87 to receptor side chain Gln-284, and an H-bond from ligand Asn-95 to the carbonyl backbone of receptor residue Asp-282.

The direct hydrogen bond interaction between Glu-96 of FGF 2 (Glu-87 of FGF 1) and Gln-285 of D3 in FGFR 2 (Gln-284 in FGFR 1) is particularly important. Ala substitution of this residue in FGF 2 leads to a 1000 fold decrease in binding.

The Kinemages

 

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:  The Unit Cell

 



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37 K

Click On KiNG to see  Calpha Trace of the Unit Cell

 

Kinemage 2: Ribbon Rendering of the FGF 1 Bound to FGFR 1c  Complex

 



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1,041 K

Click On KiNG to see Ribbon Rendering of FGF 1 Bound To FGFR 1c


Kinemage 3: Cartoon Rendering of the FGF 1 Bound to FGFR 1c Complex



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842 K

Click On KiNG to see Cartoon Rendering of FGF 1 Bound To FGFR 1c

 


  Kinemage 4: Bound and Unbound FGF 1

 

Bound and Unbound FGF1 with heparin (from 1AXM) for reference

 

View 1  the overlay
View 2  area around Glu-91
View 3  area around Glu-104
View 4  area around His-124

 



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531 K

Click On KiNG to see FGF 1: Bound and Unbound

 


       Kinemage 5: Interactions of FGF  1 at FGFR 1c Domain D2

 

Ligand-Receptor interactions include FGF 1 residues Tyr-15, Phe-17, Gly-19, Gly-20, Phe-22, His-93, Tyr-94, Leu-133, Leu-135, and Pro-136 and receptor residues Lys-163, Leu-165, Ala-167, and Pro-169, and Val-248. There is also hydrogen bonding between the FGF ligand Ser-17 backbone carbonyl and the side chain amino group of receptor Lys-183 and another hydrogen bond between the oxygen of the phenol group of ligand Tyr-15 and the backbone NH moiety of receptor Ala-167.

View 1  the complex
View 2  area around Lys-163
View 3  area around Ala-167
View 4  area around Pro-169
View 5  hydrogen bonding between ligand and receptor



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890 K

Click On KiNG to see FGF 1 Bound To FGFR 1c: D2 Interactions


Kinemage 6: Interactions between FGF 1 and the FGFR 1c Linker Between D2-D3

The hydrophobic interactions provide a distinctly non-polar local environment which increases any possible electronic interactions. The ligand residues Leu-89 and Pro-136 coupled with receptor residues Val-248 and Pro-252 provide a hydrophobic cavity surrounding the invariant polar residue, Arg-250. Ligand binding is stabilized by a network of hydrogen bonds, especially between Arg-251 and invariant Asp-282 of the receptor and between Asn-95 and Tyr-97 (which also H bonds to ligand residue Glu-87) of the ligand 

View 1  the complex
View 2  chain A ligand interactions with the D2-D3 linker region of receptor chain C
View 3  receptor D3 Asp 282 and linker residue Arg-250
View 4  ligand Asn-95 and receptor linker residue Arg-250
View 5  ligand Tyr-97 with residues Glu-87 and Asn-95.

 



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889 K

Click On KiNG to see  FGF 1 Bound To FGFR 1c Linker

 

Kinemage 7: Interactions between FGF 1 and the FGFR 1c D3 Domain

Kinemage 7: Interactions between FGF 1 and the FGFR 1 D3 Domain

Hydrophobic interactions primarily involve a cavity defined by FGFR 1 residues Val-279, Pro-285, and Ile-287. This cavity, upon FGF 1 binding, is occupied by FGF 1 residue Tyr-8. 

Hydrogen bonding stabilization of FGF ligand to receptor binding in the D3 Domain include the phenol group of Tyr-8 to the backbone carbonyl of receptor residue Pro-285, side chain of ligand residue Glu-87 to receptor side chain Gln-284, and an H-bond from ligand Asn-95 to the carbonyl backbone of receptor residue Asp-282. 

View 1  the complex
View 2  FGF 1 residue Tyr-8
View 3  FGF 1 residue Glu-49
View 4  FGF 1 residue Asn-95



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892 K

Click On KiNG to see Interactions Between FGF 1 & FGFR 1c  D3

 

Sequences:

FGF 1 
Chain A
NYKKPKLLYCSNGGHFLRILPDGTVDGTRDRSDQHIQLQLSAESVGEVYIKSTETGQYLAMDTDGLLYGSQTPNEECLFL
ERLEENHYNTYISKKHAEKNWFVGLKKNGSCKRGPRTHYGQKAILFLPLPVSSD

Chain B
NYKKPKLLYCSNGGHFLRILPDGTVDGTRDRSDQHIQLQLSAESVGEVYIKSTETGQYLAMDTDGLLYGSQTPNEECLFL
ERLEENHYNTYISKKHAEKNWFVGLKKNGSCKRGPRTHYGQKAILFLPLPVSSD


FGFR 1
Chain C
TDNTKPNRMPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSV
VPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKI
GPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEER

Chain D
TDNTKPNRMPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSV
VPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKI
GPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEER

Source:

The human sequences corresponding to the D2 and D3 domains of FGFR 1 were expressed in E.coli. The structural coordinates are from the Brookhaven Data Base file1EVT.

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FGF Site: FGF Intro     Nomenclature     Notes      References      FGF Sequences     FGFR Sequences 

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Copyright 2005-2020 by Larry P. Taylor
Molecular & Behavioral Neuroscience Institute
University of Michigan

All rights reserved

Supported by the Pritzker Neuropsychiatric Disorders Research Consortium, and by NIH Grant 5 P01 MH42251, Conte Center Grant #L99MH60398, RO1 DA13386 and the Office of Naval Research (ONR) N00014-02-1-0879 to Huda Akil & Stanley J. Watson. at the Molecular & Behavioral Neuroscience Institute.