PDBsum entry 5n6o

Protein binding

PDB id: 5n6o

Contents

Protein chains

176 a.a.

Ligands

GDP ×2

Metals

_MG ×2

Waters ×53

PDB id:

5n6o

Name:

Protein binding

Title:

Wild type human rac1-gdp

Structure:

Ras-related c3 botulinum toxin substrate 1. Chain: a, b. Synonym: cell migration-inducing gene 5 protein,ras-like protein tc25,p21-rac1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: rac1, tc25, mig5. Expressed in: escherichia coli 'bl21-gold(de3)plyss ag'. Expression_system_taxid: 866768

Resolution:

2.59Å R-factor: 0.196 R-free: 0.252

Authors:

J.Cherfils,Y.Ferrandez

Key ref:

Y.Ferrandez et al. (2017). Allosteric inhibition of the guanine nucleotide exchange factor DOCK5 by a small molecule. Sci Rep, 7, 14409. PubMed id: 29089502

Date:

15-Feb-17 Release date: 27-Dec-17

Protein chains

P63000  (RAC1_HUMAN) -  Ras-related C3 botulinum toxin substrate 1 from Homo sapiens

Seq: 192 a.a.

Struc: 176 a.a.

Enzyme reactions

• Enzyme class: E.C.3.6.5.2 - small monomeric GTPase.
• Reaction: GTP + H2O = GDP + phosphate + H⁺

GTP + H2O = GDP (Bound ligand (Het Group name = GDP) corresponds exactly) + phosphate + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

Sci Rep 7:14409 (2017)

PubMed id: 29089502

Allosteric inhibition of the guanine nucleotide exchange factor DOCK5 by a small molecule.

Y.Ferrandez, W.Zhang, F.Peurois, L.Akendengué, A.Blangy, M.Zeghouf, J.Cherfils.

ABSTRACT

Rac small GTPases and their GEFs of the DOCK family are pivotal checkpoints in development, autoimmunity and bone homeostasis, and their abnormal regulation is associated to diverse pathologies. Small molecules that inhibit their activities are therefore needed to investigate their functions. Here, we characterized the mechanism of inhibition of human DOCK5 by C21, a small molecule that inhibits mouse Dock5 in cells and blocks bone degradation in mice models of osteoporosis. We showed that the catalytic DHR2 domain of DOCK5 has a high basal GEF activity in the absence of membranes which is not regulated by a simple feedback loop. C21 blocks this activity in a non-competitive manner and is specific for DOCK5. In contrast, another Dock inhibitor, CPYPP, inhibits both DOCK5 and an unrelated GEF, Trio. To gain insight into structural features of the inhibitory mechanism of C21, we used SAXS analysis of DOCK5^DHR2and crystallographic analysis of unbound Rac1-GDP. Together, these data suggest that C21 takes advantage of intramolecular dynamics of DOCK5 and Rac1 to remodel the complex into an unproductive conformation. Based on this allosteric mechanism, we propose that diversion of intramolecular dynamics is a potent mechanism for the inhibition of multidomain regulators of small GTPases.