8b75

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CRYSTAL STRUCTURE OF HUMAN SOLUBLE ADENYLYL CYCLASE IN COMPLEX WITH THE INHIBITOR TDI-011861

Structural highlights

8b75 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.82Å
Ligands:CME, PJU
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

Soluble adenylyl cyclase (sAC: ADCY10) is an enzyme involved in intracellular signaling. Inhibition of sAC has potential therapeutic utility in a number of areas. For example, sAC is integral to successful male fertility: sAC activation is required for sperm motility and ability to undergo the acrosome reaction, two processes central to oocyte fertilization. Pharmacologic evaluation of existing sAC inhibitors for utility as on-demand, nonhormonal male contraceptives suggested that both high intrinsic potency, fast on and slow dissociation rates are essential design elements for successful male contraceptive applications. During the course of the medicinal chemistry campaign described here, we identified sAC inhibitors that fulfill these criteria and are suitable for in vivo evaluation of diverse sAC pharmacology.

Design, Synthesis, and Pharmacological Evaluation of Second-Generation Soluble Adenylyl Cyclase (sAC, ADCY10) Inhibitors with Slow Dissociation Rates.,Miller M, Rossetti T, Ferreira J, Ghanem L, Balbach M, Kaur N, Levin LR, Buck J, Kehr M, Coquille S, van den Heuvel J, Steegborn C, Fushimi M, Finkin-Groner E, Myers RW, Kargman S, Liverton NJ, Huggins DJ, Meinke PT J Med Chem. 2022 Nov 24;65(22):15208-15226. doi: 10.1021/acs.jmedchem.2c01133. , Epub 2022 Nov 8. PMID:36346696[3]

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

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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. ↑ Miller M, Rossetti T, Ferreira J, Ghanem L, Balbach M, Kaur N, Levin LR, Buck J, Kehr M, Coquille S, van den Heuvel J, Steegborn C, Fushimi M, Finkin-Groner E, Myers RW, Kargman S, Liverton NJ, Huggins DJ, Meinke PT. Design, Synthesis, and Pharmacological Evaluation of Second-Generation Soluble Adenylyl Cyclase (sAC, ADCY10) Inhibitors with Slow Dissociation Rates. J Med Chem. 2022 Nov 24;65(22):15208-15226. PMID:36346696 doi:10.1021/acs.jmedchem.2c01133

Contents


PDB ID 8b75

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OCA

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