6aj4: Difference between revisions
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The entry | ==Crystal structure of the DHR-2 domain of DOCK7 in complex with Cdc42== | ||
<StructureSection load='6aj4' size='340' side='right'caption='[[6aj4]], [[Resolution|resolution]] 3.26Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6aj4]] is a 8 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=6AJ4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6AJ4 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]] 3.256Å</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=6aj4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6aj4 OCA], [https://pdbe.org/6aj4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6aj4 RCSB], [https://www.ebi.ac.uk/pdbsum/6aj4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6aj4 ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://www.uniprot.org/uniprot/DOCK7_HUMAN DOCK7_HUMAN] Early-onset epileptic encephalopathy-cortical blindness-intellectual disability-facial dysmorphism syndrome. The disease is caused by mutations affecting the gene represented in this entry. | |||
== Function == | |||
[https://www.uniprot.org/uniprot/DOCK7_HUMAN DOCK7_HUMAN] Functions as a guanine nucleotide exchange factor (GEF), which activates Rac1 and Rac3 Rho small GTPases by exchanging bound GDP for free GTP. Does not have a GEF activity for CDC42. Required for STMN1 'Ser-15' phosphorylation during axon formation and consequently for neuronal polarization (PubMed:16982419). Has a role in pigmentation (By similarity). Involved in the regulation of cortical neurogenesis through the control of radial glial cells (RGCs) proliferation versus differentiation; negatively regulates the basal-to-apical interkinetic nuclear migration of RGCs by antagonizing the microtubule growth-promoting function of TACC3 (By similarity).[UniProtKB:Q8R1A4]<ref>PMID:16982419</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The Dedicator Of CytoKinesis (DOCK) family of atypical guanine nucleotide exchange factors activates the Rho family GTPases Rac and/or Cdc42 through DOCK homology region 2 (DHR-2). Previous structural analyses of the DHR-2 domains of DOCK2 and DOCK9 have shown that they preferentially bind Rac1 and Cdc42, respectively; however, the molecular mechanism by which DHR-2 distinguishes between these GTPases is unclear. Here we report the crystal structure of the Cdc42-bound form of the DOCK7 DHR-2 domain showing dual specificity for Rac1 and Cdc42. The structure revealed increased substrate tolerance of DOCK7 at the interfaces with switch 1 and residue 56 of Cdc42. Furthermore, molecular dynamics simulations showed a closed-to-open conformational change in the DOCK7 DHR-2 domain between the Cdc42- and Rac1-bound states by lobe B displacement. Our results suggest that lobe B acts as a sensor for identifying different switch 1 conformations and explain how DOCK7 recognizes both Rac1 and Cdc42. | |||
Structural Basis for the Dual Substrate Specificity of DOCK7 Guanine Nucleotide Exchange Factor.,Kukimoto-Niino M, Tsuda K, Ihara K, Mishima-Tsumagari C, Honda K, Ohsawa N, Shirouzu M Structure. 2019 Feb 16. pii: S0969-2126(19)30045-0. doi:, 10.1016/j.str.2019.02.001. PMID:30853411<ref>PMID:30853411</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6aj4" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Dedicator of cytokinesis protein 3D structures|Dedicator of cytokinesis protein 3D structures]] | |||
*[[GTP-binding protein 3D structures|GTP-binding protein 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Kukimoto-Niino M]] | |||
[[Category: Shirouzu M]] | |||
Latest revision as of 12:31, 22 November 2023
Crystal structure of the DHR-2 domain of DOCK7 in complex with Cdc42Crystal structure of the DHR-2 domain of DOCK7 in complex with Cdc42
Structural highlights
DiseaseDOCK7_HUMAN Early-onset epileptic encephalopathy-cortical blindness-intellectual disability-facial dysmorphism syndrome. The disease is caused by mutations affecting the gene represented in this entry. FunctionDOCK7_HUMAN Functions as a guanine nucleotide exchange factor (GEF), which activates Rac1 and Rac3 Rho small GTPases by exchanging bound GDP for free GTP. Does not have a GEF activity for CDC42. Required for STMN1 'Ser-15' phosphorylation during axon formation and consequently for neuronal polarization (PubMed:16982419). Has a role in pigmentation (By similarity). Involved in the regulation of cortical neurogenesis through the control of radial glial cells (RGCs) proliferation versus differentiation; negatively regulates the basal-to-apical interkinetic nuclear migration of RGCs by antagonizing the microtubule growth-promoting function of TACC3 (By similarity).[UniProtKB:Q8R1A4][1] Publication Abstract from PubMedThe Dedicator Of CytoKinesis (DOCK) family of atypical guanine nucleotide exchange factors activates the Rho family GTPases Rac and/or Cdc42 through DOCK homology region 2 (DHR-2). Previous structural analyses of the DHR-2 domains of DOCK2 and DOCK9 have shown that they preferentially bind Rac1 and Cdc42, respectively; however, the molecular mechanism by which DHR-2 distinguishes between these GTPases is unclear. Here we report the crystal structure of the Cdc42-bound form of the DOCK7 DHR-2 domain showing dual specificity for Rac1 and Cdc42. The structure revealed increased substrate tolerance of DOCK7 at the interfaces with switch 1 and residue 56 of Cdc42. Furthermore, molecular dynamics simulations showed a closed-to-open conformational change in the DOCK7 DHR-2 domain between the Cdc42- and Rac1-bound states by lobe B displacement. Our results suggest that lobe B acts as a sensor for identifying different switch 1 conformations and explain how DOCK7 recognizes both Rac1 and Cdc42. Structural Basis for the Dual Substrate Specificity of DOCK7 Guanine Nucleotide Exchange Factor.,Kukimoto-Niino M, Tsuda K, Ihara K, Mishima-Tsumagari C, Honda K, Ohsawa N, Shirouzu M Structure. 2019 Feb 16. pii: S0969-2126(19)30045-0. doi:, 10.1016/j.str.2019.02.001. PMID:30853411[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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