The Human FGF 1-FGFR 3c Complex

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 

The Human FGF 1-FGFR 3c Complex


The unit cell for the FGF 1-FGFR 3c complex is shown in Kinemage 1. Kinemage 2 adds main chains, main chain H-bonding, side chains, and ribbon rendering to the unit cell. Kinemage 3 is the secondary structure cartoon for the FGF 1-FGFR 3c complex. The characteristics of the unit cell for this structure are summarized at pdbsum.

The interaction between FGF ligands and the FGF receptor domain D2 is primarily hydrophobic. This involves the side chains of FGF 1 residues His-16, Tyr-30, Arg-50, Tyr-109, Ala-148, and Leu-150. Receptor residues involved in hydrophobic contacts are the side chains of Asp-150, Lys-161, Leu-163, Ala-165, Pro-167, and Leu-246. This flat contact plane of hydrophobicity is strengthened by the hydrogen bonding from the FGF 1 invariant Tyr-30 to the receptor Lys-131 side chain and two hydrogen bonds to the backbone the of Ala-165 (one each to the backbone carbonyl and amide nitrogen). Lys-131's geometry is stabilized by a further hydrogen bond to the backbone carbonyl of FGF ligand Gly-34. In addition there are two hydrogen bonds between FGF 1 residue Arg-50 and the backbone carbonyl of receptor Domain D2 residue Asp-160. (Although the backbone is resolved, the side chain for Asp-160 is disordered and unresolved.) The position of the Arg-50 is stabilized by hydrogen bonding to ligand residue His-36. This network of hydrogen bonding within the FGF ligand-receptor Domain D2 is highlighted in Kinemage 4.

Although the Linker region between D2 and D3 is short, it is well conserved and critical to ligand receptor binding Arg-248 is invariant across the four FGF receptors. This Arg residue has its position maintained for ligand interaction by a network of hydrogen bonds that involves both D2 and D3 regions of the receptor. This network provides a fairly rigid and conserved ligand-receptor binding geometry. The guanidinium group of Arg-248 makes two hydrogen bonds with FGF2: one with the backbone carbonyl oxygen of His-108 and another with the side chain carbonyl oxygen of Asn-110. An Asn-110 side chain amide in FGF 2 is also engaged in an intra-molecular hydrogen bond with Tyr-112, which in turn is hydrogen bonded to Glu-102, another invariant residue in the FGF ligand family. The side chain of Glu-102 is also hydrogen bonded to the backbone amide nitrogen of Gln-292 in the D3 domain of the receptor. The FGF 2 to FGFR 1 linker binding interactions are shown in Kinemage 5.

Finally, the side chains of Leu-246 in the D2-D3 linker and the Leu-104 of FGF 2 form a hydrophobic shelf for the aliphatic portion of the Arg-248 side chain. This, plus, the two intra-molecular hydrogen bonds between the Arg-248 guanidinium group and the side chain carboxylate of the invariant Asp-280 in receptor Domain D3 provides a stabilized, relatively rigid D2-Linker-D3 region.

The interactions between D3 and FGF 2 (Kinemage  6) occur near the linker region of the receptor. While the interactions with D2 are primarily hydrophobic, the interactions between FGF and the receptor at Domain D3 are mostly polar. The side chain of Tyr-23 in FGF 2 slides along a hydrophobic shelf defined by FGFR 3c Domain D3 residues Pro-283, Val-277, and Ile-285. The side chain of Tyr-23 hydrogen bonds to a side chain oxygen of Gln-322, which, in turn, hydrogen bonds to the side chain of ligand residue Lys-24. The ligand backbone carbonyl of Lys-24 hydrogen bonds to receptor side chain Lys-319. The backbone carbonyl of FGF 1 residue Lys-15 hydrogen bonds to side chain amide of receptor residue Gln-256. The aliphatic portion of the side chain of receptor residue Gln-256, Ile-254, and Tyr-278 with FGF ligand residue Phe-16, Leu-18 and Pro-19 add some hydrophobicity to this region to strengthen the hydrogen bonds. The backbone amide of Gly-21 hydrogen bonds to receptor side chain of Gln-320. Ligand residue Asn-22 side chain carbonyl hydrogen bonds to the receptor backbone amide of residue Ser-279. Finally, there is a unique to FGFR 3c turn-stabilizing hydrogen bond between the backbone carbonyl of residue Ala-312 and the side chain hydroxyl of Ser-325.

 

Since the N-terminus of most FGF molecules show flexibility too great to resolve with X-ray crystallization, structural studies have been done, for the most part, on FGF species with a truncated N-terminus. However, the truncated form of FGF 1 would not bind to FGF Receptor 3c. So, a more complete N-terminus was used. This resulted in an ordered N-terminus with defined interactions with the receptor domain D3. These interactions included FGF 1 hydrophobic residues Phe-16, Leu-18, Pro-19, and Pro-20 contacting receptor D3 residues Ile-254, Gln-256, Lys-276, and Tyr-278. These interactions are displayed in Kinemage 7.

 

The Kinemages

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Kinemage 1: Calpha Trace of the Unit Cell for FGF 1-FGFR 3c

 



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 19 K

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Kinemage 2: Ribbon Rendering of the Unit Cell for FGF 1-FGFR 3c

 



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579 K

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Kinemage 3: Cartoon Rendering of the Unit Cell for FGF 1-FGFR 3c

 



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 416 K

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  Kinemage 4:  Ligand-D2 Interactions for the FGF 1-FGFR 3c Complex

The interaction between FGF ligands and the FGF receptor domain D2 is primarily hydrophobic. This involves FGF 1 residues His-16, Tyr-30, Arg-50, Tyr-109, Ala-148, and Leu-150. Receptor residues involved are Asp-150, Lys-161, Leu-163, Ala-165, Pro-167, and Leu-246. There is hydrogen bonding from the FGF 1 invariant Tyr-30 to the receptor Lys-131 and two hydrogen bonds to the backbone the of Ala-165 (one each to the backbone carbonyl and amide nitrogen). Lys-131's geometry is stabilized by a further hydrogen bond to the backbone carbonyl of FGF ligand Gly-34. In addition there are two hydrogen bonds between FGF 1 residue Arg-50 and the backbone carbonyl of receptor D2 residue Asp-160. (Although the backbone is resolved, the side chain for Asp-160 is disordered and unresolved.) The position of the Arg-50 is stabilized by hydrogen bonding to ligand residue His-36


View 1 the complex
View 2 focus on Tyr-30
View 3 focus on Arg-50

 



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495 K

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Kinemage 5: Ligand-Linker Interactions for the FGF 1-FGFR 3c Complex

 

The guanidinium group of Arg-248 makes two hydrogen bonds with FGF2: one with the backbone carbonyl oxygen of His-108 and another with the side chain carbonyl oxygen of Asn-110. An Asn-110 side chain amide in FGF 2 is also engaged in an intra-molecular hydrogen bond with Tyr-112, which in turn is hydrogen bonded to Glu-102, another invariant residue in the FGF ligand family. The side chain of Glu-102 is also hydrogen bonded to the backbone amide nitrogen of Gln-292 in the D3 domain of the receptor


View 1 the complex
View 2 centers on Receptor Arg-248
View 3 centers on Ligand Tyr-112

 

 



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 494 K

Click On KiNG to see FGF 1-FGFR 3c: Linker Interactions

Kinemage 6: Ligand-D3 Interactions for the FGF 1-FGFR 3c Complex

The side chain of Tyr-23 in FGF 2 slides along a hydrophobic shelf defined by FGFR 3c Domain D3 residues Pro-283, Val-277, and Ile-285. The side chain of Tyr-23 hydrogen bonds to a side chain oxygen of Gln-322, which, in turn, hydrogen bonds to the side chain of ligand residue Lys-24. The ligand backbone carbonyl of Lys-24 hydrogen bonds to receptor side chain Lys-319. The backbone carbonyl of FGF 1 residue Lys-15 hydrogen bonds to side chain amide of receptor residue Gln-256. The aliphatic portion of the side chain of receptor residue Gln-256, Ile-254, and Tyr-278 with FGF ligand residue Phe-16, Leu-18 and Pro-19 add some hydrophobicity to this region to strengthen the hydrogen bonds. The backbone amide of Gly-21 hydrogen bonds to receptor side chain of Gln-320. Ligand residue Asn-22 side chain carbonyl hydrogen bonds to the receptor backbone amide of residue Ser-279. Finally, there is a unique to FGFR 3c turn-stabilizing hydrogen bond between the backbone carbonyl of residue Ala-312 and the side chain hydroxyl of Ser-325.


View 1 the complex
View 2 focus on Ligand Tyr-23
View 3 focus on Ligand Asn-22
View 4 hydrophobics of Ligand Phe-16, Leu-18 and Pro-19
View 5 focus on Receptor Gln-256
View 6 hydrogen bond between Receptor Ala-312 and side chain of Ser-325

 



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 496 K

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Kinemage 7: Ligand N-terminal-D3 Interactions for the FGF 1-FGFR 3c Complex

 

These interactions include FGF 1 hydrophobic residues Phe-16, Leu-18, Pro-19, and Pro-20 contacting receptor D3 residues Ile-254, Gln-256, Lys-276, and Tyr-278. 


View 1 the complex
View 2 focus on the N-Terminal
View 3 focus on hydrophobic interactions



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 493 K

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FGF 1-FGFR 3c: Ligand N-terminal-D3 Interactions

 

Sequences:

 

Chain A: FGF 1


Unresolved N-terminal: MAEG

 

X-Ray Resolved: EITTFTALTEKFNLPPGNYKKPKLLYCSNGGHFLRILPDGTVDGTRDRSDQHIQLQLSAESVGEVYIKSTETGQYL
AMDTDGLLYGSQTPNEECLFLERLEENHYNTYISKKHAEKNWFVGLKKNGSCKRGPRTHYGQKAILFLPLPVSSD

Chain B FGFR 3c


Unresolved N-terminal: MGRAAEVPGPEPGQQEQLVFGSGDAVELSCPPPGGGPMGPTVWVKDGTGLVPSERVLVGPQRLQVL

NASHEDSGAYSCRQRLTQRVLCHFSVRVTDAPSSGDDEDGEDEAEDTGVDTG

 

X-Ray Resolved: APYWTRPERMDKKLLAVPAANTVRFRCPAAGNPTPSISWLKNGREFRGEHRIGGIKLRHQQWSLVMESVVP

SDRGNYTCVVENKFGSIRQTYTLDVLERSPHRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVEVNGSKVGPDGT

PYVTVLKTAGANTTDKELEVLSLHNVTFEDAGEYTCLAGNSIGFSHHSAWLVVLPAEEE

 

Unresolved C-terminal: LVE


Source:

 

Ligands and receptors were expressed in Escherichia coli and purified by heparin affinity and ion exchange chromatography. Structural Coordinates were taken from the Brookhaven Data Base File 1RY7.

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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.