3ooi | pdb_00003ooi
Crystal Structure of Human Histone-Lysine N-methyltransferase NSD1 SET domain in Complex with S-adenosyl-L-methionine
Structural highlights
Disease[NSD1_HUMAN] Sotos syndrome;Beckwith-Wiedemann syndrome due to NSD1 mutation;5q35 microduplication syndrome;Weaver syndrome. Sotos syndrome 1 (SOTOS1) [MIM:117550]: A childhood overgrowth syndrome characterized by pre- and postnatal overgrowth, developmental delay, mental retardation, advanced bone age, and abnormal craniofacial morphology including macrodolichocephaly with frontal bossing, frontoparietal sparseness of hair, apparent hypertelorism, downslanting palpebral fissures, and facial flushing. Common oral findings include: premature eruption of teeth; high, arched palate; pointed chin and, more rarely, prognathism. Note=The disease is caused by mutations affecting the gene represented in this entry.[1] [2] [3] [4] [5] Weaver syndrome 1 (WVS1) [MIM:277590]: A syndrome of accelerated growth and osseous maturation, unusual craniofacial appearance, hoarse and low-pitched cry, and hypertonia with camptodactyly. Distinguishing features of Weaver syndrome include broad forehead and face, ocular hypertelorism, prominent wide philtrum, micrognathia, deep horizontal chin groove, and deep-set nails. In addition, carpal bone development is advanced over the rest of the hand. Note=The disease is caused by mutations affecting the gene represented in this entry.[6] [7] Beckwith-Wiedemann syndrome (BWS) [MIM:130650]: A disorder characterized by anterior abdominal wall defects including exomphalos (omphalocele), pre- and postnatal overgrowth, and macroglossia. Additional less frequent complications include specific developmental defects and a predisposition to embryonal tumors. Note=The disease is caused by mutations affecting the gene represented in this entry.[8] Note=A chromosomal aberration involving NSD1 is found in childhood acute myeloid leukemia. Translocation t(5;11)(q35;p15.5) with NUP98. Note=A chromosomal aberration involving NSD1 is found in an adult form of myelodysplastic syndrome (MDS). Insertion of NUP98 into NSD1 generates a NUP98-NSD1 fusion product. Function[NSD1_HUMAN] Histone methyltransferase. Preferentially methylates 'Lys-36' of histone H3 and 'Lys-20' of histone H4 (in vitro). Transcriptional intermediary factor capable of both negatively or positively influencing transcription, depending on the cellular context.[9] Publication Abstract from PubMedThe Sotos syndrome gene product, NSD1, is a SET domain histone methyltransferase that primarily dimethylates nucleosomal histone H3 lysine 36 (H3K36). To date, the intrinsic properties of NSD1 that determine its nucleosomal substrate selectivity and dimethyl H3K36 product specificity remain unknown. The 1.7 A structure of the catalytic domain of NSD1 presented here shows that a regulatory loop adopts a conformation that prevents free access of H3K36 to the bound S-adenosyl-l-methionine. Molecular dynamics simulation and computational docking revealed that this normally inhibitory loop can adopt an active conformation, allowing H3K36 access to the active site, and that the nucleosome may stabilize the active conformation of the regulatory loop. Hence, our study reveals an autoregulatory mechanism of NSD1 and provides insight into the molecular mechanism of the nucleosomal substrate selectivity of this disease-related H3K36 methyltransferase. The Structure of NSD1 Reveals an Autoregulatory Mechanism Underlying Histone H3K36 Methylation.,Qiao Q, Li Y, Chen Z, Wang M, Reinberg D, Xu RM J Biol Chem. 2011 Mar 11;286(10):8361-8. Epub 2010 Dec 31. PMID:21196496[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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