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90 a.a.
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105 a.a.
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242 a.a.
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* Residue conservation analysis
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PDB id:
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Hormone/growth factor
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Title:
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Crystal structure of human follicle stimulating hormone comp its receptor
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Structure:
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Glycoprotein hormones alpha chain. Chain: a, d. Synonym: follitropin alpha chain, follicle-stimulating horm chain, fsh-alpha, lutropin alpha chain, luteinizing hormone chain, lsh-alpha, thyrotropin alpha chain, thyroid-stimulat hormone alpha chain, tsh-alpha, choriogonadotropin alpha ch chorionic gonadotrophin alpha subunit, cg-alpha. Engineered: yes. Follitropin beta chain.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: cga. Expressed in: trichoplusia ni. Expression_system_taxid: 7111. Expression_system_cell_line: high 5. Gene: fshb. Gene: fshr.
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Biol. unit:
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Trimer (from
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Resolution:
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2.92Å
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R-factor:
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0.221
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R-free:
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0.259
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Authors:
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Q.R.Fan,W.A.Hendrickson
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Key ref:
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Q.R.Fan
and
W.A.Hendrickson
(2005).
Structure of human follicle-stimulating hormone in complex with its receptor.
Nature,
433,
269-277.
PubMed id:
DOI:
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Date:
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30-Oct-04
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Release date:
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25-Jan-05
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PROCHECK
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Headers
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References
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P01215
(GLHA_HUMAN) -
Glycoprotein hormones alpha chain
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Seq: Struc:
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116 a.a.
90 a.a.
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Gene Ontology (GO) functional annotation
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Cellular component
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extracellular region
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4 terms
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Biological process
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developmental growth
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21 terms
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Biochemical function
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protein binding
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5 terms
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DOI no:
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Nature
433:269-277
(2005)
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PubMed id:
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Structure of human follicle-stimulating hormone in complex with its receptor.
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Q.R.Fan,
W.A.Hendrickson.
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ABSTRACT
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Follicle-stimulating hormone (FSH) is central to reproduction in mammals. It
acts through a G-protein-coupled receptor on the surface of target cells to
stimulate testicular and ovarian functions. We present here the 2.9-A-resolution
structure of a partially deglycosylated complex of human FSH bound to the
extracellular hormone-binding domain of its receptor (FSHR(HB)). The hormone is
bound in a hand-clasp fashion to an elongated, curved receptor. The buried
interface of the complex is large (2,600 A2) and has a high charge density. Our
analysis suggests that all glycoprotein hormones bind to their receptors in this
mode and that binding specificity is mediated by key interaction sites involving
both the common alpha- and hormone-specific beta-subunits. On binding, FSH
undergoes a concerted conformational change that affects protruding loops
implicated in receptor activation. The FSH-FSHR(HB) complexes form dimers in the
crystal and at high concentrations in solution. Such dimers may participate in
transmembrane signal transduction.
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Selected figure(s)
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Figure 1.
Figure 1: Crystal structure of human FSH bound to FSHR[HB].
a, b, Ribbon diagram of the complex structure shown in two views
related by a 90° rotation about the vertical axis. FSH -chains
and -chains
are in green and cyan, respectively. FSHR[HB] is in red. The
observed N-linked carbohydrates at N52 and N78 of FSH- ,
N7 and N24 of FSH- ,
and N191 of FSHR[HB] are in yellow. Disulphide bonds are in
black. c, Schematic diagram of the topology of FSHR[HB]
structure. -Strands
are shown as arrows. Red represents strands located at the
concave face of FSHR[HB]; pink represents strands on the convex
face.
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Figure 3.
Figure 3: Interactions at the receptor-ligand interface. a,
Ribbon diagram showing the top view of the FSH-FSHR[HB] complex.
The view in the right panel is tilted to highlight the regions
of FSHR[HB] (red), and FSH- (green)
and FSH- (cyan)
chains that are involved in direct contacts at the
receptor-ligand interface. Dashed circles mark the locations of
L55 and K179 in the FSHR[HB] structure. b, Detailed views of the
interactions at the specificity pockets for L55 and K179 of
FSHR[HB]. The dotted molecular surface of FSH is shown in cyan
in each panel. c, Close-up stereo view of the interactions
between the C-terminal region of FSH- and
FSHR[HB].
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nature
(2005,
433,
269-277)
copyright 2005.
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Figures were
selected
by the author.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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G.P.Rodini,
V.K.Genro,
U.Matte,
F.S.Pereira,
J.P.Bilibio,
C.Greggianin,
C.A.Souza,
and
J.S.Cunha-Filho
(2011).
There is no complete linkage between the polymorphisms N680S and T307A of the follicular stimulating hormone receptor gene in fertile women.
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J Assist Reprod Genet, 28,
221-224.
|
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H.F.Vischer,
A.O.Watts,
S.Nijmeijer,
and
R.Leurs
(2011).
G protein-coupled receptors: walking hand-in-hand, talking hand-in-hand?
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Br J Pharmacol, 163,
246-260.
|
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|
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M.D.Lalioti
(2011).
Impact of follicle stimulating hormone receptor variants in fertility.
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Curr Opin Obstet Gynecol, 23,
158-167.
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|
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Y.Li,
A.Gu,
H.Yang,
X.Ding,
G.Ji,
C.Lu,
Y.Xia,
L.Song,
and
X.Wang
(2011).
FSH receptor gene polymorphisms in fertile and infertile Han-Chinese males.
|
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Clin Chim Acta, 412,
1048-1052.
|
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|
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C.Y.Pan,
S.Hu,
D.G.Li,
P.Ouyang,
F.H.Zhao,
and
Y.Y.Zheng
(2010).
The first ferroelectric templated borate: [Ni(en)2pip][B5O6(OH)4]2.
|
| |
Dalton Trans, 39,
5772-5773.
|
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|
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|
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G.Vassart
(2010).
An in vivo demonstration of functional G protein-coupled receptor dimers.
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| |
Proc Natl Acad Sci U S A, 107,
1819-1820.
|
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|
|
|
|
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H.Cangul,
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G.A.Kirby,
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E.Eren,
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W.Hogler,
T.G.Barrett,
and
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(2010).
Novel TSHR mutations in consanguineous families with congenital nongoitrous hypothyroidism.
|
| |
Clin Endocrinol (Oxf), 73,
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|
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|
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|
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K.Uchida,
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H.Chiba,
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and
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(2010).
Evolutionary origin of a functional gonadotropin in the pituitary of the most primitive vertebrate, hagfish.
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| |
Proc Natl Acad Sci U S A, 107,
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|
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R.Guan,
X.Wu,
X.Feng,
M.Zhang,
T.E.Hébert,
and
D.L.Segaloff
(2010).
Structural determinants underlying constitutive dimerization of unoccupied human follitropin receptors.
|
| |
Cell Signal, 22,
247-256.
|
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|
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|
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R.Latif,
K.Michalek,
S.A.Morshed,
and
T.F.Davies
(2010).
A tyrosine residue on the TSH receptor stabilizes multimer formation.
|
| |
PLoS One, 5,
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|
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|
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|
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S.Mueller,
H.Jaeschke,
R.Günther,
and
R.Paschke
(2010).
The hinge region: an important receptor component for GPHR function.
|
| |
Trends Endocrinol Metab, 21,
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|
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|
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X.Yu,
S.W.Lin,
M.Kobayashi,
and
W.Ge
(2010).
Expression of recombinant zebrafish follicle-stimulating hormone (FSH) in methylotropic yeast Pichia pastoris.
|
| |
Fish Physiol Biochem, 36,
273-281.
|
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|
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A.M.Svendsen,
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P.De Meyts,
and
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(2009).
Dimerization and negative cooperativity in the relaxin family peptide receptors.
|
| |
Ann N Y Acad Sci, 1160,
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|
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|
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D.J.Scott,
G.W.Tregear,
and
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(2009).
Modeling the primary hormone-binding site of RXFP1 and RXFP2.
|
| |
Ann N Y Acad Sci, 1160,
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|
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J.R.Powell,
D.H.Kim,
and
F.M.Ausubel
(2009).
The G protein-coupled receptor FSHR-1 is required for the Caenorhabditis elegans innate immune response.
|
| |
Proc Natl Acad Sci U S A, 106,
2782-2787.
|
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|
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|
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K.L.Hindle,
J.Bella,
and
S.C.Lovell
(2009).
Quantitative analysis and prediction of curvature in leucine-rich repeat proteins.
|
| |
Proteins, 77,
342-358.
|
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|
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|
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K.M.Bonger,
R.J.van den Berg,
A.D.Knijnenburg,
L.H.Heitman,
C.J.van Koppen,
C.M.Timmers,
H.S.Overkleeft,
and
G.A.van der Marel
(2009).
Discovery of selective luteinizing hormone receptor agonists using the bivalent ligand method.
|
| |
ChemMedChem, 4,
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|
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|
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|
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K.M.Bonger,
S.Hoogendoorn,
C.J.van Koppen,
C.M.Timmers,
H.S.Overkleeft,
and
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(2009).
Synthesis and pharmacological evaluation of dimeric follicle-stimulating hormone receptor antagonists.
|
| |
ChemMedChem, 4,
2098-2102.
|
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|
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M.Dupakuntla,
J.D.Ghosalkar,
and
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(2009).
Characterization of Peptide 20-30 of follicle stimulating hormone receptor as an antagonist of receptor activity: significance of charged residues.
|
| |
Chem Biol Drug Des, 73,
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|
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|
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|
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S.Mueller,
G.Kleinau,
M.W.Szkudlinski,
H.Jaeschke,
G.Krause,
and
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(2009).
The Superagonistic Activity of Bovine Thyroid-stimulating Hormone (TSH) and the Human TR1401 TSH Analog Is Determined by Specific Amino Acids in the Hinge Region of the Human TSH Receptor.
|
| |
J Biol Chem, 284,
16317-16324.
|
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|
|
|
|
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S.Picchietti,
M.Belardinelli,
A.R.Taddei,
A.M.Fausto,
M.Pellegrino,
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M.Rossi,
and
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(2009).
Thyroid disruptor 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) prevents internalization of TSH receptor.
|
| |
Cell Tissue Res, 336,
31-40.
|
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|
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|
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C.Selvaakumar,
D.D.Jagtap,
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K.V.Chary,
S.D.Mahale,
and
T.D.Nandedkar
(2009).
Interaction of follicle-stimulating hormone (FSH) receptor binding inhibitor-8: a novel FSH-binding inhibitor, with FSH and its receptor.
|
| |
Chem Biol Drug Des, 73,
637-643.
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A.Moore,
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M.K.Robinson,
and
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Characterization of the Structural Features and Interactions of Sclerostin: MOLECULAR INSIGHT INTO A KEY REGULATOR OF Wnt-MEDIATED BONE FORMATION.
|
| |
J Biol Chem, 284,
10890-10900.
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PDB code:
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A.A.Pioszak,
and
H.E.Xu
(2008).
Molecular recognition of parathyroid hormone by its G protein-coupled receptor.
|
| |
Proc Natl Acad Sci U S A, 105,
5034-5039.
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PDB code:
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A.De Leener,
G.Caltabiano,
S.Erkan,
M.Idil,
G.Vassart,
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Identification of the first germline mutation in the extracellular domain of the follitropin receptor responsible for spontaneous ovarian hyperstimulation syndrome.
|
| |
Hum Mutat, 29,
91-98.
|
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|
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|
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A.Zalesko,
J.Kønig,
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J.D.Wade,
R.A.Bathgate,
P.De Meyts,
and
J.Nøhr
(2008).
Negative cooperativity in H2 relaxin binding to a dimeric relaxin family peptide receptor 1.
|
| |
Mol Cell Endocrinol, 296,
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|
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|
|
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|
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B.J.Arey
(2008).
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|
| |
Endocrine, 34,
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|
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|
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|
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B.Rees Smith,
J.Sanders,
and
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(2008).
Implications of new monoclonal antibodies and the crystal structure of the TSH receptor for the treatment and management of thyroid diseases.
|
| |
Biomark Med, 2,
567-576.
|
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|
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I.S.Hagemann,
D.L.Miller,
J.M.Klco,
G.V.Nikiforovich,
and
T.J.Baranski
(2008).
Structure of the complement factor 5a receptor-ligand complex studied by disulfide trapping and molecular modeling.
|
| |
J Biol Chem, 283,
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|
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|
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|
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J.D.Funkhouser,
F.S.Moyer,
S.V.Gibson,
and
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(2008).
Molecular cloning of pituitary glycoprotein alpha-subunit and follicle stimulating hormone and chorionic gonadotropin beta-subunits from New World squirrel monkey and owl monkey.
|
| |
Gen Comp Endocrinol, 155,
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|
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|
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|
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and
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(2008).
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|
| |
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|
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|
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|
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M.Verhoef-Post,
and
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Asp330 and Tyr331 in the C-terminal cysteine-rich region of the luteinizing hormone receptor are key residues in hormone-induced receptor activation.
|
| |
J Biol Chem, 283,
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|
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|
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M.C.Lagerström,
and
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(2008).
Structural diversity of G protein-coupled receptors and significance for drug discovery.
|
| |
Nat Rev Drug Discov, 7,
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|
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|
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M.Freamat,
and
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(2008).
Glycoprotein hormone receptors in the sea lamprey Petromyzon marinus.
|
| |
Zoolog Sci, 25,
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| |
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| |
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A functional transmembrane complex: the luteinizing hormone receptor with bound ligand and G protein.
|
| |
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(2007).
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|
| |
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| |
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|
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(2007).
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|
| |
J Biol Chem, 282,
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|
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|
|
|
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(2007).
Pituitary glycoprotein hormone receptors in non-endocrine organs.
|
| |
Trends Endocrinol Metab, 18,
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|
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|
|
|
|
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H.C.Matozo,
M.A.Santos,
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(2007).
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|
| |
Biophys J, 92,
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|
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|
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The most recent references are shown first.
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so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
code is
shown on the right.
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