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Science 308 (5724): 1020-1023

Copyright © 2005 by the American Association for the Advancement of Science

The Structure of a pH-Sensing Mycobacterial Adenylyl Cyclase Holoenzyme

Ivo Tews,1*{dagger} Felix Findeisen,1* Irmgard Sinning,1 Anita Schultz,2 Joachim E. Schultz,2 Jürgen U. Linder2{dagger}

Abstract: Class III adenylyl cyclases contain catalytic and regulatory domains, yet structural insight into their interactions is missing. We show that the mycobacterial adenylyl cyclase Rv1264 is rendered a pH sensor by its N-terminal domain. In the structure of the inhibited state, catalytic and regulatory domains share a large interface involving catalytic residues. In the structure of the active state, the two catalytic domains rotate by 55° to form two catalytic sites at their interface. Two {alpha} helices serve as molecular switches. Mutagenesis is consistent with a regulatory role of the structural transition, and we suggest that the transition is regulated by pH.

1 Biochemiezentrum der Universität Heidelberg, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.
2 Pharmazeutisches Institut, Pharmazeutische Biochemie, Morgenstelle 8, 72076 Tübingen, Germany.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: ivo.tews{at} (I.T.); juergen.linder{at} (J.U.L.)

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