PDBsum entry: 1pwa

Hormone/growth factor

PDB-id

1pwa


	Asymmetric unit

Contents

Description

Header details

Protein chain

Ligands

SO4

TRS

GOL

Waters ×267

* Residue conservation analysis

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		Biological unit, hexamer (as deduced by PQS)

PDB id:

1pwa

Name:

Hormone/growth factor

Title:

Crystal structure of fibroblast growth factor 19

Structure:

Fibroblast growth factor-19. Chain: a. Synonym: fgf-19. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: fgf19. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biological unit:

Hexamer (from PQS)

UniProt:

O95750 (FGF19_HUMAN)

Seq:

216 a.a.

Struc:

123 a.a.

Key:		PfamA domain
		Secondary structure			CATH domain

Resolution:

1.30Å

R-factor:

0.181

R-free:

0.195

Authors:

N.J.Harmer,L.Pellegrini,D.Chirgadze,J.Fernandez-Recio, T.L.Blundell

Key ref:

N.J.Harmer et al. (2004). The crystal structure of fibroblast growth factor (FGF) 19 reveals novel features of the FGF family and offers a structural basis for its unusual receptor affinity.. Biochemistry, 43, 629-640. [PubMed id: 14730967] [DOI: 10.1021/bi035320k]

Date:

01-Jul-03

Release date:

27-Jan-04

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Key reference

DOI no: 10.1021/bi035320k Biochemistry 43:629-640 (2004)

PubMed id: 14730967

The crystal structure of fibroblast growth factor (FGF) 19 reveals novel features of the FGF family and offers a structural basis for its unusual receptor affinity.

N.J.Harmer, L.Pellegrini, D.Chirgadze, J.Fernandez-Recio, T.L.Blundell.

ABSTRACT

The 22 members of the FGF family have been implicated in cell proliferation, differentiation, survival, and migration. They are required for both development and maintenance of vertebrates, demonstrating an exquisite pattern of affinities for both protein and proteoglycan receptors. FGF19, one of the most divergent human FGFs, is unique in binding solely to one receptor, FGFR4. We have used molecular replacement to solve the crystal structure of FGF19 at 1.3 A resolution using five superimposed FGF structures as the search model. The structure shows that two novel disulfide bonds found in FGF19, one of which appears to be conserved among several of the other FGFs, stabilize extended loops. The key heparin-binding loops of FGF19 have radically different conformations and charge patterns, compared to other FGFs, correlating with the unusually low affinity of FGF19 for heparin. A model for the complex of FGF19 with FGFR4 demonstrates that unique sequences in both FGF19 and FGFR4 are key to the formation of the complex. The structure therefore offers a clear explanation for the unusual affinity of FGF19 for FGFR4 alone.

Literature references that cite this PDB file's key reference

PubMed id Reference

19319846 H.Kurosu, and M.Kuro-O (2009).
Endocrine fibroblast growth factors as regulators of metabolic homeostasis.

Biofactors, 35, 52-60.

19277467 M.Rydén (2009).
Fibroblast growth factor 21: an overview from a clinical perspective.

Cell Mol Life Sci, 66, 2067-2073.

19117008 R.Micanovic, D.W.Raches, J.D.Dunbar, D.A.Driver, H.A.Bina, C.D.Dickinson, and A.Kharitonenkov (2009).
Different roles of N- and C- termini in the functional activity of FGF21.

J Cell Physiol, 219, 227-234.

19706524 X.Wu, H.Ge, B.Lemon, J.Weiszmann, J.Gupte, N.Hawkins, X.Li, J.Tang, R.Lindberg, and Y.Li (2009).
Selective activation of FGFR4 by an FGF19 variant does not improve glucose metabolism in ob/ob mice.

Proc Natl Acad Sci U S A, 106, 14379-14384.

18186042 B.A.Kwiatkowski, I.Kirillova, R.E.Richard, D.Israeli, and Z.Yablonka-Reuveni (2008).
FGFR4 and its novel splice form in myogenic cells: Interplay of glycosylation and tyrosine phosphorylation.

J Cell Physiol, 215, 803-817.

18660672 H.Kurosu, and M.Kuro-o (2008).
The Klotho gene family and the endocrine fibroblast growth factors.

Curr Opin Nephrol Hypertens, 17, 368-372.

17599042 L.R.Desnoyers, R.Pai, R.E.Ferrando, K.Hötzel, T.Le, J.Ross, R.Carano, A.D'Souza, J.Qing, I.Mohtashemi, A.Ashkenazi, and D.M.French (2008).
Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models.

Oncogene, 27, 85-97.

18625063 U.Borello, I.Cobos, J.E.Long, C.Murre, and J.L.Rubenstein (2008).
FGF15 promotes neurogenesis and opposes FGF8 function during neocortical development.

Neural Develop, 3, 17.

17627937 B.C.Lin, M.Wang, C.Blackmore, and L.R.Desnoyers (2007).
Liver-specific activities of FGF19 require Klotho beta.

J Biol Chem, 282, 27277-27284.

17623664 H.Kurosu, M.Choi, Y.Ogawa, A.S.Dickson, R.Goetz, A.V.Eliseenkova, M.Mohammadi, K.P.Rosenblatt, S.A.Kliewer, and M.Kuro-o (2007).
Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21.

J Biol Chem, 282, 26687-26695.

17339340 R.Goetz, A.Beenken, O.A.Ibrahimi, J.Kalinina, S.K.Olsen, A.V.Eliseenkova, C.Xu, T.A.Neubert, F.Zhang, R.J.Linhardt, X.Yu, K.E.White, T.Inagaki, S.A.Kliewer, M.Yamamoto, H.Kurosu, Y.Ogawa, M.Kuro-o, B.Lanske, M.S.Razzaque, and M.Mohammadi (2007).
Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members.

Mol Cell Biol, 27, 3417-3428.

PDB codes: 2p23 2p39

17711860 X.Wu, H.Ge, J.Gupte, J.Weiszmann, G.Shimamoto, J.Stevens, N.Hawkins, B.Lemon, W.Shen, J.Xu, M.M.Veniant, Y.S.Li, R.Lindberg, J.L.Chen, H.Tian, and Y.Li (2007).
Co-receptor requirements for fibroblast growth factor-19 signaling.

J Biol Chem, 282, 29069-29072.

16937240 A.Canales-Mayordomo, R.Fayos, J.Angulo, R.Ojeda, M.Martín-Pastor, P.M.Nieto, M.Martín-Lomas, R.Lozano, G.Giménez-Gallego, and J.Jiménez-Barbero (2006).
Backbone dynamics of a biologically active human FGF-1 monomer, complexed to a hexasaccharide heparin-analogue, by 15N NMR relaxation methods.

J Biomol NMR, 35, 225-239.

16315317 Y.Luo, S.Ye, M.Kan, and W.L.McKeehan (2006).
Structural specificity in a FGF7-affinity purified heparin octasaccharide required for formation of a complex with FGF7 and FGFR2IIIb.

J Cell Biochem, 97, 1241-1258.

15943563 C.Chen, S.Patel, S.Corisdeo, X.Liu, H.Micolochick, J.Xue, Q.Yang, Y.Lei, B.Wang, and D.Soltis (2005).
Generation and characterization of a panel of monoclonal antibodies specific for human fibroblast growth factor receptor 4 (FGFR4).

Hybridoma (Larchmt), 24, 152-159.

15750181 C.Yu, F.Wang, C.Jin, X.Huang, and W.L.McKeehan (2005).
Independent repression of bile acid synthesis and activation of c-Jun N-terminal kinase (JNK) by activated hepatocyte fibroblast growth factor receptor 4 (FGFR4) and bile acids.

J Biol Chem, 280, 17707-17714.

15921496 H.Kurose, M.Okamoto, M.Shimizu, T.Bito, C.Marcelle, S.Noji, and H.Ohuchi (2005).
FGF19-FGFR4 signaling elaborates lens induction with the FGF8-L-Maf cascade in the chick embryo.

Dev Growth Differ, 47, 213-223.

15632068 O.A.Ibrahimi, B.K.Yeh, A.V.Eliseenkova, F.Zhang, S.K.Olsen, M.Igarashi, S.A.Aaronson, R.J.Linhardt, and M.Mohammadi (2005).
Analysis of mutations in fibroblast growth factor (FGF) and a pathogenic mutation in FGF receptor (FGFR) provides direct evidence for the symmetric two-end model for FGFR dimerization.

Mol Cell Biol, 25, 671-684.

16076373 T.Yamashita (2005).
Structural and biochemical properties of fibroblast growth factor 23.

Ther Apher Dial, 9, 313-318.

The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.