8grh | pdb_00008grh

Crystal structure of a constitutively active mutant of the alpha gamma heterodimer of human IDH3 in complex with CIT

spinqualitylabelsall models 8grh, resolution 2.51Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8grh is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CIT Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function IDH3A_HUMAN Publication Abstract from PubMed Human NAD-dependent isocitrate dehydrogenase or IDH3 (HsIDH3) catalyzes the decarboxylation of isocitrate into alpha-ketoglutarate in the tricarboxylic acid (TCA) cycle. It consists of three types of subunits (alpha, beta, and gamma), and exists and functions as the (alphabetaalphagamma)(2) heterooctamer. HsIDH3 is regulated allosterically and/or competitively by numerous metabolites including CIT, ADP, ATP, and NADH. Our previous studies have revealed the molecular basis for the activity and regulation of the alphabeta and alphagamma heterodimers. However, the molecular mechanism for the allosteric activation of the HsIDH3 holoenzyme remains elusive. In this work, we report the crystal structures of the alphabeta and alphagamma heterodimers and the (alphabetaalphagamma)(2) heterooctamer containing an alpha-Q139A mutation in the clasp domain which renders all the heterodimers and the heterooctamer constitutively active in the absence of activators. Our structural analysis shows that the alpha-Q139A mutation alters the hydrogen-bonding network at the heterodimer-heterodimer interface in a manner similar to that in the activator-bound alphagamma heterodimer. This alteration not only stabilizes the active sites of both alpha(Q139A)beta and alpha(Q139A)gamma heterodimers in active conformations but also induces conformational changes of the pseudo-allosteric site of the alpha(Q139A)beta heterodimer enabling it to bind activators. In addition, the alpha(Q139A)(ICT+Ca+NAD)beta(NAD) structure presents the first pseudo-Michaelis complex of HsIDH3 which allows us to identify the key residues involved in the binding of cofactor, substrate and metal ion. Our structural and biochemical data together reveal new insights into the molecular mechanisms for allosteric regulation and the catalytic reaction of HsIDH3. Structures of a constitutively active mutant of human IDH3 reveal new insights into the mechanisms of allosteric activation and the catalytic reaction.,Chen X, Sun P, Liu Y, Shen S, Ma T, Ding J J Biol Chem. 2022 Nov 11:102695. doi: 10.1016/j.jbc.2022.102695. PMID:36375638 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Proteopedia Page Contributors and Editors (what is this?)

OCA