4D0N

AKAP13 (AKAP-Lbc) RhoGEF domain in complex with RhoA

Summary for 4D0N

• Entry DOI: 10.2210/pdb4d0n/pdb
• Related: 4D0O
• Descriptor: TRANSFORMING PROTEIN RHOA, A-KINASE ANCHOR PROTEIN 13, GUANOSINE-5'-DIPHOSPHATE, ... (6 entities in total)
• Functional Keywords: cell cycle, akap13, lbc, akap-lbc, gef, rhogef, dh domain, ph domain
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Cell membrane; Lipid-anchor; Cytoplasmic side: P61586; Cytoplasm: Q12802
• Total number of polymer chains: 2
• Total formula weight: 65354.15

Authors

Abdul Azeez, K.R.,Shrestha, L.,Krojer, T.,Allerston, C.,von Delft, F.,Bountra, C.,Arrowsmith, C.,Edwards, A.M.,Knapp, S.,Klussmann, E.,Elkins, J.M. (deposition date: 2014-04-29, release date: 2014-05-21, Last modification date: 2024-05-08)

Primary citation

Abdul Azeez, K.R.,Knapp, S.,Fernandes, J.M.P.,Klussmann, E.,Elkins, J.M.
The Crystal Structure of the Rhoa : Akap-Lbc Dh-Ph Domain Complex.
Biochem.J., 464:231-, 2014

PubMed Abstract: The RhoGEF (Rho GTPase guanine-nucleotide-exchange factor) domain of AKAP-Lbc (A-kinase-anchoring protein-Lbc, also known as AKAP13) catalyses nucleotide exchange on RhoA and is involved in the development of cardiac hypertrophy. The RhoGEF activity of AKAP-Lbc has also been implicated in cancer. We have determined the X-ray crystal structure of the complex between RhoA-GDP and the AKAP-Lbc RhoGEF [DH (Dbl-homologous)-PH (pleckstrin homology)] domain to 2.1 Å (1 Å = 0.1 nm) resolution. The structure reveals important differences compared with related RhoGEF proteins such as leukaemia-associated RhoGEF. Nucleotide-exchange assays comparing the activity of the DH-PH domain to the DH domain alone showed no role for the PH domain in nucleotide exchange, which is explained by the RhoA-AKAP-Lbc structure. Comparison with a structure of the isolated AKAP-Lbc DH domain revealed a change in conformation of the N-terminal 'GEF switch' region upon binding to RhoA. Isothermal titration calorimetry showed that AKAP-Lbc has only micromolar affinity for RhoA, which combined with the presence of potential binding pockets for small molecules on AKAP-Lbc, raises the possibility of targeting AKAP-Lbc with GEF inhibitors.

PubMed: 25186459
DOI: 10.1042/BJ20140606

Experimental method

X-RAY DIFFRACTION (2.1 Å)