View source for 1waq


==Crystal structure of human Growth and Differentiation Factor 5 (GDF-5)==
<StructureSection load='1waq' size='340' side='right'caption='[[1waq]], [[Resolution|resolution]] 2.28&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1waq]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1WAQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1WAQ FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.28&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1waq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1waq OCA], [https://pdbe.org/1waq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1waq RCSB], [https://www.ebi.ac.uk/pdbsum/1waq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1waq ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/GDF5_HUMAN GDF5_HUMAN] Defects in GDF5 are the cause of acromesomelic chondrodysplasia Grebe type (AMDG) [MIM:[https://omim.org/entry/200700 200700]. Acromesomelic chondrodysplasias are rare hereditary skeletal disorders characterized by short stature, very short limbs, and hand/foot malformations. The severity of limb abnormalities increases from proximal to distal with profoundly affected hands and feet showing brachydactyly and/or rudimentary fingers (knob-like fingers). AMDG is an autosomal recessive form characterized by normal axial skeletons and missing or fused skeletal elements within the hands and feet.<ref>PMID:9288098</ref>   Defects in GDF5 are the cause of acromesomelic chondrodysplasia Hunter-Thompson type (AMDH) [MIM:[https://omim.org/entry/201250 201250]. AMDH is an autosomal recessive form of dwarfism. Patients have limb abnormalities, with the middle and distal segments being most affected and the lower limbs more affected than the upper. AMDH is characterized by normal axial skeletons and missing or fused skeletal elements within the hands and feet.  Defects in GDF5 are the cause of brachydactyly type C (BDC) [MIM:[https://omim.org/entry/113100 113100]. BDC is an autosomal dominant disorder characterized by an abnormal shortness of the fingers and toes. Note=Some BDC patients with GDF5 mutations also manifest clinical features of ASPED angel-shaped phalango-epiphyseal dysplasia (ASPED), an autosomal dominant skeletal abnormality characterized by a typical angel-shaped phalanx, brachydactyly, specific radiological findings, abnormal dentition, hip dysplasia, and delayed bone age. This suggests that BDC and ASPED are part of the same clinical spectrum (PubMed:22828468).<ref>PMID:22828468</ref> <ref>PMID:14735582</ref>   Defects in GDF5 are the cause of Du Pan syndrome (DPS) [MIM:[https://omim.org/entry/228900 228900]; also known as fibular hypoplasia and complex brachydactyly. Du Pan syndrome is a rare autosomal recessive condition characterized by absence of the fibulae and severe acromesomelic limb shortening with small, non-functional toes. Although milder, the phenotype resembles the autosomal recessive Hunter-Thompson and Grebe types of acromesomelic chondrodysplasia.<ref>PMID:12121354</ref> <ref>PMID:16222676</ref> <ref>PMID:18629880</ref>   Defects in GDF5 are a cause of symphalangism proximal syndrome (SYM1) [MIM:[https://omim.org/entry/185800 185800]. SYM1 is characterized by the hereditary absence of the proximal interphalangeal (PIP) joints (Cushing symphalangism). Severity of PIP joint involvement diminishes towards the radial side. Distal interphalangeal joints are less frequently involved and metacarpophalangeal joints are rarely affected whereas carpal bone malformation and fusion are common. In the lower extremities, tarsal bone coalition is common. Conducive hearing loss is seen and is due to fusion of the stapes to the petrous part of the temporal bone.<ref>PMID:16127465</ref> <ref>PMID:16892395</ref> <ref>PMID:18283415</ref>   Defects in GDF5 are the cause of multiple synostoses syndrome type 2 (SYNS2) [MIM:[https://omim.org/entry/610017 610017]. Multiple synostoses syndrome is an autosomal dominant condition characterized by progressive joint fusions of the fingers, wrists, ankles and cervical spine, characteristic facies and progressive conductive deafness.[:]<ref>PMID:16532400</ref>   Defects in GDF5 are a cause of brachydactyly type A2 (BDA2) [MIM:[https://omim.org/entry/112600 112600]. Brachydactylies (BDs) are a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. They have been classified on an anatomic and genetic basis into five groups, A to E, including three subgroups (A1 to A3) that usually manifest as autosomal dominant traits.<ref>PMID:16127465</ref> <ref>PMID:18203755</ref>   Genetic variations in GDF5 are associated with susceptibility to osteoarthritis type 5 (OS5) [MIM:[https://omim.org/entry/612400 612400]. Osteoarthritis is a degenerative disease of the joints characterized by degradation of the hyaline articular cartilage and remodeling of the subchondral bone with sclerosis. Clinical symptoms include pain and joint stiffness often leading to significant disability and joint replacement.  Defects in GDF5 may be a cause of brachydactyly type A1 (BDA1) [MIM:[https://omim.org/entry/112500 112500]. Brachydactylies (BDs) are a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. They have been classified on an anatomic and genetic basis into five groups, A to E, including three subgroups (A1 to A3) that usually manifest as autosomal dominant traits.<ref>PMID:20683927</ref> 
== Function ==
[https://www.uniprot.org/uniprot/GDF5_HUMAN GDF5_HUMAN] Could be involved in bone and cartilage formation. Chondrogenic signaling is mediated by the high-affinity receptor BMPR1B.<ref>PMID:15530414</ref> <ref>PMID:19229295</ref> 
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/wa/1waq_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1waq ConSurf].
<div style="clear:both"></div>
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== Publication Abstract from PubMed ==
Growth and differentiation factor 5 (GDF-5), a member of the TGF-beta superfamily, is involved in many developmental processes, like chondrogenesis and joint formation. Mutations in GDF-5 lead to diseases, e.g. chondrodysplasias like Hunter-Thompson, Grebe and DuPan syndromes and brachydactyly. Similar to other TGF-beta superfamily members, GDF-5 transmits signals through binding to two different types of membrane-bound serine-/threonine-kinase receptors termed type I and type II. In contrast to the large number of ligands, only seven type I and five type II receptors have been identified to date, implicating a limited promiscuity in ligand-receptor interaction. However, in contrast to other members of the TGF-beta superfamily, GDF-5 shows a pronounced specificity in type I receptor interaction in cross-link experiments binding only to BMP receptor IB (BMPR-IB). In mice, deletion of either GDF-5 or BMPR-IB results in a similar phenotype, indicating that GDF-5 signaling is highly dependent on BMPR-IB. Here, we demonstrate by biosensor analysis that GDF-5 also binds to BMP receptor IA (BMPR-IA) but with approximately 12-fold lower affinity. Structural and mutational analyses revealed a single residue of GDF-5, Arg57 located in the pre-helix loop, being solely responsible for the high binding specificity to BMPR-IB. In contrast to wild-type GDF-5, variant GDF-5R57A interacts with BMPR-IA and BMPR-IB with a comparable high binding affinity. These results provide important insights into how receptor-binding specificity is generated at the molecular level and might be useful for the generation of receptor subtype specific activators or inhibitors.

A single residue of GDF-5 defines binding specificity to BMP receptor IB.,Nickel J, Kotzsch A, Sebald W, Mueller TD J Mol Biol. 2005 Jun 24;349(5):933-47. Epub 2005 Apr 22. PMID:15890363<ref>PMID:15890363</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 1waq" style="background-color:#fffaf0;"></div>

==See Also==
*[[Growth differentiation factor 3D STRUCTURES|Growth differentiation factor 3D STRUCTURES]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Mueller TD]]
[[Category: Nickel J]]
[[Category: Sebald W]]