8d32

Mycobacterium tuberculosis pduO-type ATP:cobalamin adenosyltransferase bound to 5-deoxyadenosylrhodibalamin and PPPi

spinqualitylabelsall models 8d32, resolution 1.85Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8d32 is a 1 chain structure with sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.85Å Ligands: 3PO, 5AD, MG, SF0 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PDUO_MYCTU Publication Abstract from PubMed In mammals, cobalamin is an essential cofactor that is delivered by a multitude of chaperones in an elaborate trafficking pathway to two client enzymes, methionine synthase and methylmalonyl-CoA mutase (MMUT). Rhodibalamins, the rhodium analogs of cobalamins, have been described as antimetabolites due to their ability to inhibit bacterial growth. In this study, we have examined the reactivity of adenosylrhodibalamin (AdoRhbl) with two key human chaperones, MMACHC (also known as CblC) and adenosyltransferase (MMAB, also known as ATR), and with the human and Mycobacterium tuberculosis MMUT. We demonstrate that while AdoRhbl binds tightly to all four proteins, the Rh-carbon bond is resistant to homolytic (on MMAB and MMUT) as well as heterolytic (on MMACHC) rupture. On the other hand, MMAB catalyzes Rh-carbon bond formation, converting rhodi(I)balamin in the presence of ATP to AdoRhbl. We report the first crystal structure of a rhodibalamin (AdoRhbl) bound to a B(12) protein, i.e., MMAB, in the presence of triphosphate, which shows a weakened but intact Rh-carbon bond. The structure provides insights into how MMAB cleaves the corresponding Co-carbon bond in a sacrificial homolytic reaction that purportedly functions as a cofactor sequestration strategy. Collectively, the study demonstrates that while the noble metal substitution of cobalt by rhodium sets up structural mimicry, it compromises chemistry, which could be exploited for targeting human and bacterial B(12) chaperones and enzymes. A Noble Metal Substitution Leads to B(12) Cofactor Mimicry by a Rhodibalamin.,Ruetz M, Mascarenhas R, Widner F, Kieninger C, Koutmos M, Krautler B, Banerjee R Biochemistry. 2024 Aug 6;63(15):1955-1962. doi: 10.1021/acs.biochem.4c00216. Epub , 2024 Jul 16. PMID:39012171 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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