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'''Unreleased structure'''
==Co-crystal structure of SHP2 in complex with a Cefsulodin derivative==
 
<StructureSection load='4rdd' size='340' side='right' caption='[[4rdd]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
The entry 4rdd is ON HOLD  until Paper Publication
== Structural highlights ==
 
<table><tr><td colspan='2'>[[4rdd]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RDD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RDD FirstGlance]. <br>
Authors: Zhang, Z.Y., Yu, Z.H., He, R., Zhang, R.Y.
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3LU:1-({(2R)-4-CARBOXY-2-[(R)-CARBOXY{[(2R)-2-PHENYL-2-SULFOACETYL]AMINO}METHYL]-3,6-DIHYDRO-2H-1,3-THIAZIN-5-YL}METHYL)PYRIDINIUM'>3LU</scene></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>
Description: Co-crystal structure of SHP2 in complex with a Cefsulodin derivative
<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=4rdd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rdd OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4rdd RCSB], [http://www.ebi.ac.uk/pdbsum/4rdd PDBsum]</span></td></tr>
[[Category: Unreleased Structures]]
</table>
[[Category: Zhang, R.Y]]
== Disease ==
[[Category: Yu, Z.H]]
[[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> 
[[Category: Zhang, Z.Y]]
== 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> 
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Protein-tyrosine-phosphatase]]
[[Category: He, R]]
[[Category: He, R]]
[[Category: Yu, Z H]]
[[Category: Zhang, R Y]]
[[Category: Zhang, Z Y]]
[[Category: Hydrolase]]
[[Category: Hydrolase-hydrolase inhibitor complex]]

Revision as of 15:19, 1 July 2015

Co-crystal structure of SHP2 in complex with a Cefsulodin derivativeCo-crystal structure of SHP2 in complex with a Cefsulodin derivative

Structural highlights

4rdd is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Activity:Protein-tyrosine-phosphatase, with EC number 3.1.3.48
Resources:FirstGlance, OCA, RCSB, PDBsum

Disease

[PTN11_HUMAN] Defects in PTPN11 are the cause of LEOPARD syndrome type 1 (LEOPARD1) [MIM: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.[1] [2] [3] [4] [5] [6] [7] Defects in PTPN11 are the cause of Noonan syndrome type 1 (NS1) [MIM: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.[8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] Defects in PTPN11 are a cause of juvenile myelomonocytic leukemia (JMML) [MIM: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.[20] Defects in PTPN11 are a cause of metachondromatosis (MC) [MIM: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.[21]

Function

[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.[22] [23] [24]

References

  1. ↑ Digilio MC, Conti E, Sarkozy A, Mingarelli R, Dottorini T, Marino B, Pizzuti A, Dallapiccola B. Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet. 2002 Aug;71(2):389-94. Epub 2002 Jun 7. PMID:12058348 doi:S0002-9297(07)60483-2
  2. ↑ Conti E, Dottorini T, Sarkozy A, Tiller GE, Esposito G, Pizzuti A, Dallapiccola B. A novel PTPN11 mutation in LEOPARD syndrome. Hum Mutat. 2003 Jun;21(6):654. PMID:14961557 doi:10.1002/humu.9149
  3. ↑ Yoshida R, Nagai T, Hasegawa T, Kinoshita E, Tanaka T, Ogata T. Two novel and one recurrent PTPN11 mutations in LEOPARD syndrome. Am J Med Genet A. 2004 Nov 1;130A(4):432-4. PMID:15389709 doi:10.1002/ajmg.a.30281
  4. ↑ Keren B, Hadchouel A, Saba S, Sznajer Y, Bonneau D, Leheup B, Boute O, Gaillard D, Lacombe D, Layet V, Marlin S, Mortier G, Toutain A, Beylot C, Baumann C, Verloes A, Cave H. PTPN11 mutations in patients with LEOPARD syndrome: a French multicentric experience. J Med Genet. 2004 Nov;41(11):e117. PMID:15520399 doi:10.1136/jmg.2004.021451
  5. ↑ Sarkozy A, Conti E, Digilio MC, Marino B, Morini E, Pacileo G, Wilson M, Calabro R, Pizzuti A, Dallapiccola B. Clinical and molecular analysis of 30 patients with multiple lentigines LEOPARD syndrome. J Med Genet. 2004 May;41(5):e68. PMID:15121796
  6. ↑ Kalidas K, Shaw AC, Crosby AH, Newbury-Ecob R, Greenhalgh L, Temple IK, Law C, Patel A, Patton MA, Jeffery S. Genetic heterogeneity in LEOPARD syndrome: two families with no mutations in PTPN11. J Hum Genet. 2005;50(1):21-5. Epub 2004 Dec 10. PMID:15690106 doi:10.1007/s10038-004-0212-x
  7. ↑ Ucar C, Calyskan U, Martini S, Heinritz W. Acute myelomonocytic leukemia in a boy with LEOPARD syndrome (PTPN11 gene mutation positive). J Pediatr Hematol Oncol. 2006 Mar;28(3):123-5. PMID:16679933 doi:10.1097/01.mph.0000199590.21797.0b
  8. ↑ Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, van der Burgt I, Crosby AH, Ion A, Jeffery S, Kalidas K, Patton MA, Kucherlapati RS, Gelb BD. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001 Dec;29(4):465-8. PMID:11704759 doi:10.1038/ng772
  9. ↑ Tartaglia M, Kalidas K, Shaw A, Song X, Musat DL, van der Burgt I, Brunner HG, Bertola DR, Crosby A, Ion A, Kucherlapati RS, Jeffery S, Patton MA, Gelb BD. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002 Jun;70(6):1555-63. Epub 2002 May 1. PMID:11992261 doi:10.1086/340847
  10. ↑ Maheshwari M, Belmont J, Fernbach S, Ho T, Molinari L, Yakub I, Yu F, Combes A, Towbin J, Craigen WJ, Gibbs R. PTPN11 mutations in Noonan syndrome type I: detection of recurrent mutations in exons 3 and 13. Hum Mutat. 2002 Oct;20(4):298-304. PMID:12325025 doi:10.1002/humu.10129
  11. ↑ Kosaki K, Suzuki T, Muroya K, Hasegawa T, Sato S, Matsuo N, Kosaki R, Nagai T, Hasegawa Y, Ogata T. PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) mutations in seven Japanese patients with Noonan syndrome. J Clin Endocrinol Metab. 2002 Aug;87(8):3529-33. PMID:12161469
  12. ↑ Schollen E, Matthijs G, Gewillig M, Fryns JP, Legius E. PTPN11 mutation in a large family with Noonan syndrome and dizygous twinning. Eur J Hum Genet. 2003 Jan;11(1):85-8. PMID:12529711 doi:10.1038/sj.ejhg.5200915
  13. ↑ Musante L, Kehl HG, Majewski F, Meinecke P, Schweiger S, Gillessen-Kaesbach G, Wieczorek D, Hinkel GK, Tinschert S, Hoeltzenbein M, Ropers HH, Kalscheuer VM. Spectrum of mutations in PTPN11 and genotype-phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio-facio-cutaneous syndrome. Eur J Hum Genet. 2003 Feb;11(2):201-6. PMID:12634870 doi:10.1038/sj.ejhg.5200935
  14. ↑ Kondoh T, Ishii E, Aoki Y, Shimizu T, Zaitsu M, Matsubara Y, Moriuchi H. Noonan syndrome with leukaemoid reaction and overproduction of catecholamines: a case report. Eur J Pediatr. 2003 Jul;162(7-8):548-9. Epub 2003 May 9. PMID:12739139 doi:10.1007/s00431-003-1227-6
  15. ↑ Sarkozy A, Conti E, Seripa D, Digilio MC, Grifone N, Tandoi C, Fazio VM, Di Ciommo V, Marino B, Pizzuti A, Dallapiccola B. Correlation between PTPN11 gene mutations and congenital heart defects in Noonan and LEOPARD syndromes. J Med Genet. 2003 Sep;40(9):704-8. PMID:12960218
  16. ↑ Tartaglia M, Niemeyer CM, Fragale A, Song X, Buechner J, Jung A, Hahlen K, Hasle H, Licht JD, Gelb BD. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet. 2003 Jun;34(2):148-50. PMID:12717436 doi:10.1038/ng1156
  17. ↑ Bertola DR, Pereira AC, de Oliveira PS, Kim CA, Krieger JE. Clinical variability in a Noonan syndrome family with a new PTPN11 gene mutation. Am J Med Genet A. 2004 Nov 1;130A(4):378-83. PMID:15384080 doi:10.1002/ajmg.a.30270
  18. ↑ Bertola DR, Pereira AC, Passetti F, de Oliveira PS, Messiaen L, Gelb BD, Kim CA, Krieger JE. Neurofibromatosis-Noonan syndrome: molecular evidence of the concurrence of both disorders in a patient. Am J Med Genet A. 2005 Jul 30;136(3):242-5. PMID:15948193 doi:10.1002/ajmg.a.30813
  19. ↑ Ko JM, Kim JM, Kim GH, Yoo HW. PTPN11, SOS1, KRAS, and RAF1 gene analysis, and genotype-phenotype correlation in Korean patients with Noonan syndrome. J Hum Genet. 2008;53(11-12):999-1006. doi: 10.1007/s10038-008-0343-6. Epub 2008, Nov 20. PMID:19020799 doi:10.1007/s10038-008-0343-6
  20. ↑ Tartaglia M, Niemeyer CM, Fragale A, Song X, Buechner J, Jung A, Hahlen K, Hasle H, Licht JD, Gelb BD. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet. 2003 Jun;34(2):148-50. PMID:12717436 doi:10.1038/ng1156
  21. ↑ Sobreira NL, Cirulli ET, Avramopoulos D, Wohler E, Oswald GL, Stevens EL, Ge D, Shianna KV, Smith JP, Maia JM, Gumbs CE, Pevsner J, Thomas G, Valle D, Hoover-Fong JE, Goldstein DB. Whole-genome sequencing of a single proband together with linkage analysis identifies a Mendelian disease gene. PLoS Genet. 2010 Jun 17;6(6):e1000991. doi: 10.1371/journal.pgen.1000991. PMID:20577567 doi:10.1371/journal.pgen.1000991
  22. ↑ Miao H, Burnett E, Kinch M, Simon E, Wang B. Activation of EphA2 kinase suppresses integrin function and causes focal-adhesion-kinase dephosphorylation. Nat Cell Biol. 2000 Feb;2(2):62-9. PMID:10655584 doi:10.1038/35000008
  23. ↑ Jakob S, Schroeder P, Lukosz M, Buchner N, Spyridopoulos I, Altschmied J, Haendeler J. Nuclear protein tyrosine phosphatase Shp-2 is one important negative regulator of nuclear export of telomerase reverse transcriptase. J Biol Chem. 2008 Nov 28;283(48):33155-61. doi: 10.1074/jbc.M805138200. Epub 2008, Oct 1. PMID:18829466 doi:10.1074/jbc.M805138200
  24. ↑ Lee HH, Chang ZF. Regulation of RhoA-dependent ROCKII activation by Shp2. J Cell Biol. 2008 Jun 16;181(6):999-1012. doi: 10.1083/jcb.200710187. PMID:18559669 doi:10.1083/jcb.200710187

4rdd, resolution 1.60Å

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