Origin of asymmetry in adenylyl cyclases: Structures of Mycobacterium tuberculosis Rv1900c

Sangita C. Sinha, Martina Wetterer, Stephen R. Sprang, Joachim E. Schultz, Jur̈gen U. Linder

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)663-673
Number of pages11
JournalEMBO Journal
Volume24
Issue number4
DOIs
StatePublished - Feb 23 2005

Keywords

  • Adenylyl cyclase
  • Crystal structure
  • Half-of-sites-reactivity
  • Homodimer
  • Mycobacterium tuberculosis

Fingerprint

Dive into the research topics of 'Origin of asymmetry in adenylyl cyclases: Structures of Mycobacterium tuberculosis Rv1900c'. Together they form a unique fingerprint.

Cite this