Origin of asymmetry in adenylyl cyclases: structures of Mycobacterium tuberculosis Rv1900c
Open Access
- 27 January 2005
- journal article
- Published by Springer Nature in The EMBO Journal
- Vol. 24 (4) , 663-673
- https://doi.org/10.1038/sj.emboj.7600573
Abstract
Rv1900c, a Mycobacterium tuberculosis adenylyl cyclase, is composed of an N‐terminal α/β‐hydrolase domain and a C‐terminal cyclase homology domain. It has an unusual 7% guanylyl cyclase side‐activity. A canonical substrate‐defining lysine and a catalytic asparagine indispensable for mammalian adenylyl cyclase activity correspond to N342 and H402 in Rv1900c. Mutagenic analysis indicates that these residues are dispensable for activity of Rv1900c. Structures of the cyclase homology domain, solved to 2.4 Å both with and without an ATP analog, form isologous, but asymmetric homodimers. The noncanonical N342 and H402 do not interact with the substrate. Subunits of the unliganded open dimer move substantially upon binding substrate, forming a closed dimer similar to the mammalian cyclase heterodimers, in which one interfacial active site is occupied and the quasi‐dyad‐related active site is occluded. This asymmetry indicates that both active sites cannot simultaneously be catalytically active. Such a mechanism of half‐of‐sites‐reactivity suggests that mammalian heterodimeric adenylyl cyclases may have evolved from gene duplication of a primitive prokaryote‐type cyclase, followed by loss of function in one active site.Keywords
This publication has 65 references indexed in Scilit:
- High-resolution Structures Reveal Details of Domain Closure and “Half-of-sites-reactivity” in Escherichia coli Aspartate β-Semialdehyde DehydrogenaseJournal of Molecular Biology, 2004
- A Survey of Nucleotide Cyclases in Actinobacteria: Unique Domain Organization and Expansion of the Class III Cyclase Family inMycobacterium tuberculosisComparative and Functional Genomics, 2004
- CyaG, a Novel Cyanobacterial Adenylyl Cyclase and a Possible Ancestor of Mammalian Guanylyl CyclasesJournal of Biological Chemistry, 2001
- Identification of a novel adenylate cyclase in the ruminal anaerobe, Prevotella ruminicola D31dFEMS Microbiology Letters, 1998
- Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequenceNature, 1998
- [20] Processing of X-ray diffraction data collected in oscillation modePublished by Elsevier ,1997
- Complexity and Diversity of Mammalian Adenylyl CyclasesAnnual Review of Pharmacology and Toxicology, 1996
- Precision Substrate Targeting of Protein KinasesJournal of Biological Chemistry, 1996
- Complexity and Diversity of Mammalian Adenylyl CyclasesAnnual Review of Pharmacology and Toxicology, 1996
- Aspartate receptors of Escherichia coli and Salmonella typhimurium bind ligand with negative and half-of-the-sites cooperativityBiochemistry, 1994