8be2

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Crystal structure of SOS1-Nanobody77

Structural highlights

8be2 is a 2 chain structure with sequence from Homo sapiens and Lama glama. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.897935Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

SOS1_HUMAN Defects in SOS1 are the cause of gingival fibromatosis 1 (GGF1) [MIM:135300; also known as GINGF1. Gingival fibromatosis is a rare overgrowth condition characterized by a benign, slowly progressive, nonhemorrhagic, fibrous enlargement of maxillary and mandibular keratinized gingiva. GGF1 is usually transmitted as an autosomal dominant trait, although sporadic cases are common.[1] Defects in SOS1 are the cause of Noonan syndrome type 4 (NS4) [MIM:610733. NS4 is an autosomal dominant disorder characterized by dysmorphic facial features, short stature, hypertelorism, cardiac anomalies, deafness, motor delay, and a bleeding diathesis. It is a genetically heterogeneous and relatively common syndrome, with an estimated incidence of 1 in 1000-2500 live births. Rarely, NS4 is associated with juvenile myelomonocytic leukemia (JMML). SOS1 mutations engender a high prevalence of pulmonary valve disease; atrial septal defects are less common.[2] [3] [4] [5] [6] [7] [8] [9]

Function

SOS1_HUMAN Promotes the exchange of Ras-bound GDP by GTP.

Publication Abstract from PubMed

Protein-protein interactions (PPIs) are central in cell metabolism but research tools for the structural and functional characterization of these PPIs are often missing. Here we introduce broadly applicable immunization (Cross-link PPIs and immunize llamas, ChILL) and selection strategies (Display and co-selection, DisCO) for the discovery of diverse nanobodies that either stabilize or disrupt PPIs in a single experiment. We apply ChILL and DisCO to identify competitive, connective, or fully allosteric nanobodies that inhibit or facilitate the formation of the SOS1*RAS complex and modulate the nucleotide exchange rate on this pivotal GTPase in vitro as well as RAS signalling in cellulo. One of these connective nanobodies fills a cavity that was previously identified as the binding pocket for a series of therapeutic lead compounds. The long complementarity-determining region (CDR3) that penetrates this binding pocket serves as pharmacophore for extending the repertoire of potential leads.

Allosteric nanobodies to study the interactions between SOS1 and RAS.,Fischer B, Uchanski T, Sheryazdanova A, Gonzalez S, Volkov AN, Brosens E, Zogg T, Kalichuk V, Ballet S, Versees W, Sablina AA, Pardon E, Wohlkonig A, Steyaert J Nat Commun. 2024 Jul 23;15(1):6214. doi: 10.1038/s41467-024-50349-2. PMID:39043660[10]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. ↑ Hart TC, Zhang Y, Gorry MC, Hart PS, Cooper M, Marazita ML, Marks JM, Cortelli JR, Pallos D. A mutation in the SOS1 gene causes hereditary gingival fibromatosis type 1. Am J Hum Genet. 2002 Apr;70(4):943-54. Epub 2002 Feb 26. PMID:11868160 doi:S0002-9297(07)60301-2
  2. ↑ Roberts AE, Araki T, Swanson KD, Montgomery KT, Schiripo TA, Joshi VA, Li L, Yassin Y, Tamburino AM, Neel BG, Kucherlapati RS. Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nat Genet. 2007 Jan;39(1):70-4. Epub 2006 Dec 3. PMID:17143285 doi:ng1926
  3. ↑ Tartaglia M, Pennacchio LA, Zhao C, Yadav KK, Fodale V, Sarkozy A, Pandit B, Oishi K, Martinelli S, Schackwitz W, Ustaszewska A, Martin J, Bristow J, Carta C, Lepri F, Neri C, Vasta I, Gibson K, Curry CJ, Siguero JP, Digilio MC, Zampino G, Dallapiccola B, Bar-Sagi D, Gelb BD. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet. 2007 Jan;39(1):75-9. Epub 2006 Dec 13. PMID:17143282 doi:10.1038/ng1939
  4. ↑ 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
  5. ↑ Hanna N, Parfait B, Talaat IM, Vidaud M, Elsedfy HH. SOS1: a new player in the Noonan-like/multiple giant cell lesion syndrome. Clin Genet. 2009 Jun;75(6):568-71. doi: 10.1111/j.1399-0004.2009.01149.x. Epub, 2009 May 5. PMID:19438935 doi:10.1111/j.1399-0004.2009.01149.x
  6. ↑ Longoni M, Moncini S, Cisternino M, Morella IM, Ferraiuolo S, Russo S, Mannarino S, Brazzelli V, Coi P, Zippel R, Venturin M, Riva P. Noonan syndrome associated with both a new Jnk-activating familial SOS1 and a de novo RAF1 mutations. Am J Med Genet A. 2010 Sep;152A(9):2176-84. doi: 10.1002/ajmg.a.33564. PMID:20683980 doi:10.1002/ajmg.a.33564
  7. ↑ Fabretto A, Kutsche K, Harmsen MB, Demarini S, Gasparini P, Fertz MC, Zenker M. Two cases of Noonan syndrome with severe respiratory and gastroenteral involvement and the SOS1 mutation F623I. Eur J Med Genet. 2010 Sep-Oct;53(5):322-4. doi: 10.1016/j.ejmg.2010.07.011. Epub , 2010 Jul 29. PMID:20673819 doi:10.1016/j.ejmg.2010.07.011
  8. ↑ Denayer E, Devriendt K, de Ravel T, Van Buggenhout G, Smeets E, Francois I, Sznajer Y, Craen M, Leventopoulos G, Mutesa L, Vandecasseye W, Massa G, Kayserili H, Sciot R, Fryns JP, Legius E. Tumor spectrum in children with Noonan syndrome and SOS1 or RAF1 mutations. Genes Chromosomes Cancer. 2010 Mar;49(3):242-52. doi: 10.1002/gcc.20735. PMID:19953625 doi:10.1002/gcc.20735
  9. ↑ Lepri F, De Luca A, Stella L, Rossi C, Baldassarre G, Pantaleoni F, Cordeddu V, Williams BJ, Dentici ML, Caputo V, Venanzi S, Bonaguro M, Kavamura I, Faienza MF, Pilotta A, Stanzial F, Faravelli F, Gabrielli O, Marino B, Neri G, Silengo MC, Ferrero GB, Torrrente I, Selicorni A, Mazzanti L, Digilio MC, Zampino G, Dallapiccola B, Gelb BD, Tartaglia M. SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype-phenotype correlations. Hum Mutat. 2011 Jul;32(7):760-72. doi: 10.1002/humu.21492. Epub 2011 Apr 28. PMID:21387466 doi:10.1002/humu.21492
  10. ↑ Fischer B, Uchański T, Sheryazdanova A, Gonzalez S, Volkov AN, Brosens E, Zögg T, Kalichuk V, Ballet S, Versées W, Sablina AA, Pardon E, Wohlkönig A, Steyaert J. Allosteric nanobodies to study the interactions between SOS1 and RAS. Nat Commun. 2024 Jul 23;15(1):6214. PMID:39043660 doi:10.1038/s41467-024-50349-2

Contents


PDB ID 8be2

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