View source for 6cms


==Closed structure of active SHP2 mutant E76K bound to SHP099 inhibitor==
<StructureSection load='6cms' size='340' side='right' caption='[[6cms]], [[Resolution|resolution]] 2.68&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6cms]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CMS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CMS FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5OD:6-(4-AZANYL-4-METHYL-PIPERIDIN-1-YL)-3-[2,3-BIS(CHLORANYL)PHENYL]PYRAZIN-2-AMINE'>5OD</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PTPN11, PTP2C, SHPTP2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Protein-tyrosine-phosphatase Protein-tyrosine-phosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.3.48 3.1.3.48] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6cms FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cms OCA], [http://pdbe.org/6cms PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6cms RCSB], [http://www.ebi.ac.uk/pdbsum/6cms PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6cms ProSAT]</span></td></tr>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/PTN11_HUMAN PTN11_HUMAN]] Defects in PTPN11 are the cause of LEOPARD syndrome type 1 (LEOPARD1) [MIM:[http://omim.org/entry/151100 151100]]. It is an autosomal dominant disorder allelic with Noonan syndrome. The acronym LEOPARD stands for lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and deafness.<ref>PMID:12058348</ref> <ref>PMID:14961557</ref> <ref>PMID:15389709</ref> <ref>PMID:15520399</ref> <ref>PMID:15121796</ref> <ref>PMID:15690106</ref> <ref>PMID:16679933</ref>   Defects in PTPN11 are the cause of Noonan syndrome type 1 (NS1) [MIM:[http://omim.org/entry/163950 163950]]. Noonan syndrome (NS) is a disorder characterized by dysmorphic facial features, short stature, hypertelorism, cardiac anomalies, deafness, motor delay, and a bleeding diathesis. Some patients with Noonan syndrome type 1 develop multiple giant cell lesions of the jaw or other bony or soft tissues, which are classified as pigmented villomoduolar synovitis (PVNS) when occurring in the jaw or joints. Note=Mutations in PTPN11 account for more than 50% of the cases. Rarely, NS is associated with juvenile myelomonocytic leukemia (JMML). NS1 inheritance is autosomal dominant.<ref>PMID:11704759</ref> <ref>PMID:11992261</ref> <ref>PMID:12325025</ref> <ref>PMID:12161469</ref> <ref>PMID:12529711</ref> <ref>PMID:12634870</ref> <ref>PMID:12739139</ref> <ref>PMID:12960218</ref> <ref>PMID:12717436</ref> <ref>PMID:15384080</ref> <ref>PMID:15948193</ref> <ref>PMID:19020799</ref>   Defects in PTPN11 are a cause of juvenile myelomonocytic leukemia (JMML) [MIM:[http://omim.org/entry/607785 607785]]. JMML is a pediatric myelodysplastic syndrome that constitutes approximately 30% of childhood cases of myelodysplastic syndrome (MDS) and 2% of leukemia. It is characterized by leukocytosis with tissue infiltration and in vitro hypersensitivity of myeloid progenitors to granulocyte-macrophage colony stimulating factor.<ref>PMID:12717436</ref>   Defects in PTPN11 are a cause of metachondromatosis (MC) [MIM:[http://omim.org/entry/156250 156250]]. It is a skeletal disorder with radiologic fetarures of both multiple exostoses and Ollier disease, characterized by the presence of multiple enchondromas and osteochondroma-like lesions.<ref>PMID:20577567</ref>  
== Function ==
[[http://www.uniprot.org/uniprot/PTN11_HUMAN PTN11_HUMAN]] Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus. Dephosphorylates ROCK2 at Tyr-722 resulting in stimulatation of its RhoA binding activity.<ref>PMID:10655584</ref> <ref>PMID:18829466</ref> <ref>PMID:18559669</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Protein tyrosine phosphatase SHP2 functions as a key regulator of cell cycle control, and activating mutations cause several cancers. Here, we dissect the energy landscape of wild-type SHP2 and the oncogenic mutation E76K. NMR spectroscopy and X-ray crystallography reveal that wild-type SHP2 exchanges between closed, inactive and open, active conformations. E76K mutation shifts this equilibrium toward the open state. The previously unknown open conformation is characterized, including the active-site WPD loop in the inward and outward conformations. Binding of the allosteric inhibitor SHP099 to E76K mutant, despite much weaker, results in an identical structure as the wild-type complex. A conformational selection to the closed state reduces drug affinity which, combined with E76K's much higher activity, demands significantly greater SHP099 concentrations to restore wild-type activity levels. The differences in structural ensembles and drug-binding kinetics of cancer-associated SHP2 forms may stimulate innovative ideas for developing more potent inhibitors for activated SHP2 mutants.

Mechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2.,Padua RAP, Sun Y, Marko I, Pitsawong W, Stiller JB, Otten R, Kern D Nat Commun. 2018 Oct 30;9(1):4507. doi: 10.1038/s41467-018-06814-w. PMID:30375376<ref>PMID:30375376</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6cms" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Protein-tyrosine-phosphatase]]
[[Category: Kern, D]]
[[Category: Marko, I]]
[[Category: Padua, R A.P]]
[[Category: Pitsawong, W]]
[[Category: Sun, Y]]
[[Category: Active mutant]]
[[Category: Hydrolase]]
[[Category: Hydrolase-hydrolase inhibitor complex]]
[[Category: Inactive state]]
[[Category: Protein tyrosine phosphatase]]
[[Category: Src homology domain 2]]