5iv3

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Crystal structure of human soluble adenylyl cyclase in complex with alpha,beta-methyleneadenosine-5'-triphosphate and the allosteric inhibitor LRE1

Structural highlights

5iv3 is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:ACT, APC, CA, CL, EDO, GOL, LRI, PEG
NonStd Res:CME
Activity:Adenylate cyclase, with EC number 4.6.1.1
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[ADCYA_HUMAN] Idiopathic hypercalciuria. Disease susceptibility is associated with variations affecting the gene represented in this entry.

Function

[ADCYA_HUMAN] Soluble adenylyl cyclase that has a critical role in mammalian spermatogenesis. Produces the cAMP which mediates in part the cAMP-responsive nuclear factors indispensable for maturation of sperm in the epididymis. Induces capacitation, the maturational process that sperm undergo prior to fertilization. May be the bicarbonate sensor. Involved in ciliary beat regulation.[1] [2]

Publication Abstract from PubMed

The prototypical second messenger cAMP regulates a wide variety of physiological processes. It can simultaneously mediate diverse functions by acting locally in independently regulated microdomains. In mammalian cells, two types of adenylyl cyclase generate cAMP: G-protein-regulated transmembrane adenylyl cyclases and bicarbonate-, calcium- and ATP-regulated soluble adenylyl cyclase (sAC). Because each type of cyclase regulates distinct microdomains, methods to distinguish between them are needed to understand cAMP signaling. We developed a mass-spectrometry-based adenylyl cyclase assay, which we used to identify a new sAC-specific inhibitor, LRE1. LRE1 bound to the bicarbonate activator binding site and inhibited sAC via a unique allosteric mechanism. LRE1 prevented sAC-dependent processes in cellular and physiological systems, and it will facilitate exploration of the therapeutic potential of sAC inhibition.

Discovery of LRE1 as a specific and allosteric inhibitor of soluble adenylyl cyclase.,Ramos-Espiritu L, Kleinboelting S, Navarrete FA, Alvau A, Visconti PE, Valsecchi F, Starkov A, Manfredi G, Buck H, Adura C, Zippin JH, van den Heuvel J, Glickman JF, Steegborn C, Levin LR, Buck J Nat Chem Biol. 2016 Aug 22. doi: 10.1038/nchembio.2151. PMID:27547922[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
9 reviews cite this structure
International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases.
Dessauer et al. (2017)
8 more
35 other articles
No citations found

References

  1. ↑ Geng W, Wang Z, Zhang J, Reed BY, Pak CY, Moe OW. Cloning and characterization of the human soluble adenylyl cyclase. Am J Physiol Cell Physiol. 2005 Jun;288(6):C1305-16. Epub 2005 Jan 19. PMID:15659711 doi:http://dx.doi.org/10.1152/ajpcell.00584.2004
  2. ↑ Schmid A, Sutto Z, Nlend MC, Horvath G, Schmid N, Buck J, Levin LR, Conner GE, Fregien N, Salathe M. Soluble adenylyl cyclase is localized to cilia and contributes to ciliary beat frequency regulation via production of cAMP. J Gen Physiol. 2007 Jul;130(1):99-109. PMID:17591988 doi:http://dx.doi.org/jgp.200709784
  3. ↑ Ramos-Espiritu L, Kleinboelting S, Navarrete FA, Alvau A, Visconti PE, Valsecchi F, Starkov A, Manfredi G, Buck H, Adura C, Zippin JH, van den Heuvel J, Glickman JF, Steegborn C, Levin LR, Buck J. Discovery of LRE1 as a specific and allosteric inhibitor of soluble adenylyl cyclase. Nat Chem Biol. 2016 Aug 22. doi: 10.1038/nchembio.2151. PMID:27547922 doi:http://dx.doi.org/10.1038/nchembio.2151

Contents


5iv3, resolution 1.86Å

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