View source for 5ehp


==Non-receptor Protein Tyrosine Phosphatase SHP2 in Complex with Allosteric Inhibitor SHP836==
<StructureSection load='5ehp' size='340' side='right'caption='[[5ehp]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5ehp]] is a 2 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=5EHP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5EHP 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]] 1.85&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5OA:5-[2,3-BIS(CHLORANYL)PHENYL]-2-[(3~{R},5~{S})-3,5-DIMETHYLPIPERAZIN-1-YL]PYRIMIDIN-4-AMINE'>5OA</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=5ehp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ehp OCA], [https://pdbe.org/5ehp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ehp RCSB], [https://www.ebi.ac.uk/pdbsum/5ehp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ehp ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/PTN11_HUMAN PTN11_HUMAN] Defects in PTPN11 are the cause of LEOPARD syndrome type 1 (LEOPARD1) [MIM:[https://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:[https://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:[https://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:[https://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 ==
[https://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 ==
SHP2 is a nonreceptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also purportedly plays an important role in the programed cell death pathway (PD-1/PD-L1). As an oncoprotein associated with multiple cancer-related diseases, as well as a potential immunomodulator, controlling SHP2 activity is of significant therapeutic interest. Recently in our labs, a small molecule inhibitor of SHP2 was identified as an allosteric modulator that stabilizes the auto-inhibited conformation of SHP2. A high throughput screen was performed to identify progressable chemical matter and X-ray crystallography revealed the location of binding in a previously undisclosed allosteric binding pocket. Structure-based drug design was employed to optimize for SHP2 inhibition and several new protein-ligand interactions were characterized. These studies culminated in the discovery of 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine (SHP099), a potent, selective, orally bioavailable, and efficacious SHP2 inhibitor.

Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor.,Garcia Fortanet J, Chen CH, Chen YP, Chen Z, Deng Z, Firestone B, Fekkes P, Fodor M, Fortin PD, Fridrich C, Grunenfelder D, Ho S, Kang ZB, Karki R, Kato M, Keen N, LaBonte LR, Larrow J, Lenoir F, Liu G, Liu S, Lombardo F, Majumdar D, Meyer MJ, Palermo M, Perez LB, Pu M, Ramsey T, Sellers WR, Shultz MD, Stams T, Towler CS, Wang P, Williams SL, Zhang JH, LaMarche MJ J Med Chem. 2016 Jun 27. PMID:27347692<ref>PMID:27347692</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5ehp" style="background-color:#fffaf0;"></div>

==See Also==
*[[Tyrosine phosphatase 3D structures|Tyrosine phosphatase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Fodor M]]
[[Category: Stams T]]