View source for 3mxw


==Crystal structure Sonic hedgehog bound to the 5E1 fab fragment==
<StructureSection load='3mxw' size='340' side='right'caption='[[3mxw]], [[Resolution|resolution]] 1.83&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3mxw]] is a 3 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=3MXW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3MXW 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]] 1.83&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=3mxw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3mxw OCA], [https://pdbe.org/3mxw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3mxw RCSB], [https://www.ebi.ac.uk/pdbsum/3mxw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3mxw ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/SHH_HUMAN SHH_HUMAN] Defects in SHH are the cause of microphthalmia isolated with coloboma type 5 (MCOPCB5) [MIM:[https://omim.org/entry/611638 611638]. Microphthalmia is a clinically heterogeneous disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues. Ocular abnormalities like opacities of the cornea and lens, scaring of the retina and choroid, cataract and other abnormalities like cataract may also be present. Ocular colobomas are a set of malformations resulting from abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure).<ref>PMID:12503095</ref>   Defects in SHH are the cause of holoprosencephaly type 3 (HPE3) [MIM:[https://omim.org/entry/142945 142945]. Holoprosencephaly (HPE) [MIM:[https://omim.org/entry/236100 236100] is the most common structural anomaly of the brain, in which the developing forebrain fails to correctly separate into right and left hemispheres. Holoprosencephaly is genetically heterogeneous and associated with several distinct facies and phenotypic variability. The majority of HPE3 cases are apparently sporadic, although clear examples of autosomal dominant inheritance have been described. Interestingly, up to 30% of obligate carriers of HPE3 gene in autosomal dominant pedigrees are clinically unaffected.<ref>PMID:8896572</ref> <ref>PMID:9302262</ref> <ref>PMID:10441331</ref> <ref>PMID:10556296</ref> <ref>PMID:11479728</ref> <ref>PMID:15107988</ref> <ref>PMID:15221788</ref> <ref>PMID:15942952</ref> <ref>PMID:15942953</ref> <ref>PMID:16282375</ref> <ref>PMID:17001669</ref> <ref>PMID:19603532</ref>   Defects in SHH are a cause of solitary median maxillary central incisor (SMMCI) [MIM:[https://omim.org/entry/147250 147250]. SMMCI is a rare dental anomaly characterized by the congenital absence of one maxillary central incisor.<ref>PMID:11471164</ref> <ref>PMID:15103725</ref>   Defects in SHH are the cause of triphalangeal thumb-polysyndactyly syndrome (TPTPS) [MIM:[https://omim.org/entry/174500 174500]. TPTPS is an autosomal dominant syndrome characterized by a wide spectrum of pre- and post-axial abnormalities due to altered SHH expression pattern during limb development. TPTPS mutations have been mapped to the 7q36 locus in the LMBR1 gene which contains in its intron 5 a long-range cis-regulatory element of SHH expression.<ref>PMID:12837695</ref> 
== Function ==
[https://www.uniprot.org/uniprot/SHH_HUMAN SHH_HUMAN] Binds to the patched (PTC) receptor, which functions in association with smoothened (SMO), to activate the transcription of target genes. In the absence of SHH, PTC represses the constitutive signaling activity of SMO. Also regulates another target, the gli oncogene. Intercellular signal essential for a variety of patterning events during development: signal produced by the notochord that induces ventral cell fate in the neural tube and somites, and the polarizing signal for patterning of the anterior-posterior axis of the developing limb bud. Displays both floor plate- and motor neuron-inducing activity. The threshold concentration of N-product required for motor neuron induction is 5-fold lower than that required for floor plate induction (By similarity).
== 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/mx/3mxw_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=3mxw ConSurf].
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== Publication Abstract from PubMed ==
Proper hedgehog (Hh) signaling is crucial for embryogenesis and tissue regeneration. Dysregulation of this pathway is associated with several types of cancer. The monoclonal antibody 5E1 is a Hh pathway inhibitor that has been extensively used to elucidate vertebrate Hh biology due to its ability to block binding of the three mammalian Hh homologs to the receptor, Patched1 (Ptc1). Here, we engineered a murine:human chimeric 5E1 (ch5E1) with similar Hh-binding properties to the original murine antibody. Using biochemical, biophysical, and x-ray crystallographic studies, we show that, like the regulatory receptors Cdon and Hedgehog-interacting protein (Hhip), ch5E1 binding to Sonic hedgehog (Shh) is enhanced by calcium ions. In the presence of calcium and zinc ions, the ch5E1 binding affinity increases 10-20-fold to tighter than 1 nm primarily because of a decrease in the dissociation rate. The co-crystal structure of Shh bound to the Fab fragment of ch5E1 reveals that 5E1 binds at the pseudo-active site groove of Shh with an epitope that largely overlaps with the binding site of its natural receptor antagonist Hhip. Unlike Hhip, the side chains of 5E1 do not directly coordinate the Zn(2+) cation in the pseudo-active site, despite the modest zinc-dependent increase in 5E1 affinity for Shh. Furthermore, to our knowledge, the ch5E1 Fab-Shh complex represents the first structure of an inhibitor antibody bound to a metalloprotease fold.

Hedgehog pathway antagonist 5E1 binds hedgehog at the pseudo-active site.,Maun HR, Wen X, Lingel A, de Sauvage FJ, Lazarus RA, Scales SJ, Hymowitz SG J Biol Chem. 2010 Aug 20;285(34):26570-80. Epub 2010 May 26. PMID:20504762<ref>PMID:20504762</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 3mxw" style="background-color:#fffaf0;"></div>

==See Also==
*[[Sonic hedgehog 3D structures|Sonic hedgehog 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Hymowitz SG]]
[[Category: Maun HR]]