3CE6

Crystal structure of Mycobacterium tuberculosis S-adenosyl-L-homocysteine hydrolase in ternary complex with NAD and adenosine

Summary for 3CE6

• Entry DOI: 10.2210/pdb3ce6/pdb
• Related: 1LI4 2ZIZ 2ZJ0 2ZJ1
• Descriptor: Adenosylhomocysteinase, ADENOSINE, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, ... (4 entities in total)
• Functional Keywords: protein-substrate complex, dimer of dimers, nad binding domain, 37 amino acid insertional region, hydrolase, one-carbon metabolism
• Biological source: Mycobacterium tuberculosis
• Cellular location: Cytoplasm (By similarity): P60176
• Total number of polymer chains: 4
• Total formula weight: 220747.54

Authors

Reddy, M.C.M.,Gokulan, K.,Shetty, N.D.,Owen, J.L.,Ioerger, T.R.,Sacchettini, J.C. (deposition date: 2008-02-28, release date: 2008-09-16, Last modification date: 2023-08-30)

Primary citation

Reddy, M.C.,Kuppan, G.,Shetty, N.D.,Owen, J.L.,Ioerger, T.R.,Sacchettini, J.C.
Crystal structures of Mycobacterium tuberculosis S-adenosyl-L-homocysteine hydrolase in ternary complex with substrate and inhibitors.
Protein Sci., 17:2134-2144, 2008

PubMed Abstract: S-adenosylhomocysteine hydrolase (SAHH) is a ubiquitous enzyme that plays a central role in methylation-based processes by maintaining the intracellular balance between S-adenosylhomocysteine (SAH) and S-adenosylmethionine. We report the first prokaryotic crystal structure of SAHH, from Mycobacterium tuberculosis (Mtb), in complex with adenosine (ADO) and nicotinamide adenine dinucleotide. Structures of complexes with three inhibitors are also reported: 3'-keto aristeromycin (ARI), 2-fluoroadenosine, and 3-deazaadenosine. The ARI complex is the first reported structure of SAHH complexed with this inhibitor, and confirms the oxidation of the 3' hydroxyl to a planar keto group, consistent with its prediction as a mechanism-based inhibitor. We demonstrate the in vivo enzyme inhibition activity of the three inhibitors and also show that 2-fluoradenosine has bactericidal activity. While most of the residues lining the ADO-binding pocket are identical between Mtb and human SAHH, less is known about the binding mode of the homocysteine (HCY) appendage of the full substrate. We report the 2.0 A resolution structure of the complex of SAHH cocrystallized with SAH. The most striking change in the structure is that binding of HCY forces a rotation of His363 around the backbone to flip out of contact with the 5' hydroxyl of the ADO and opens access to a nearby channel that leads to the surface. This complex suggests that His363 acts as a switch that opens up to permit binding of substrate, then closes down after release of the cleaved HCY. Differences in the entrance to this access channel between human and Mtb SAHH are identified.

PubMed: 18815415
DOI: 10.1110/ps.038125.108

Experimental method

X-RAY DIFFRACTION (1.6 Å)