PDBsum entry 5iv4

Lyase

PDB id: 5iv4

Contents

Protein chain

461 a.a.

Ligands

LRI

ACT ×2

EDO ×5

DMS ×4

PEG

GOL

Metals

_CL

Waters ×358

PDB id:

5iv4

Name:

Lyase

Title:

Crystal structure of the human soluble adenylyl cyclase in complex with the allosteric inhibitor lre1

Structure:

Adenylate cyclase type 10. Chain: a. Synonym: ah-related protein,adenylate cyclase homolog,germ cell soluble adenylyl cyclase,sac,testicular soluble adenylyl cyclase. Engineered: yes. Other_details: cys255 modified by bme which is in the purification buffer

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: adcy10, sac. Expressed in: trichoplusia ni. Expression_system_taxid: 7111

Resolution:

1.79Å R-factor: 0.162 R-free: 0.206

Authors:

S.Kleinboelting,C.Steegborn

Key ref:

L.Ramos-Espiritu et al. (2016). Discovery of LRE1 as a specific and allosteric inhibitor of soluble adenylyl cyclase. Nat Chem Biol, 12, 838-844. PubMed id: 27547922 DOI: 10.1038/nchembio.2151

Date:

18-Mar-16 Release date: 17-Aug-16

Protein chain

Q96PN6  (ADCYA_HUMAN) -  Adenylate cyclase type 10 from Homo sapiens

Seq: 1610 a.a.

Struc: 461 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.4.6.1.1 - adenylate cyclase.
• Reaction: ATP = 3',5'-cyclic AMP + diphosphate

ATP = 3',5'-cyclic AMP (Bound ligand (Het Group name = LRI) matches with 48.15% similarity) + diphosphate

• Cofactor: Pyridoxal 5'-phosphate

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1038/nchembio.2151

Nat Chem Biol 12:838-844 (2016)

PubMed id: 27547922

Discovery of LRE1 as a specific and allosteric inhibitor of soluble adenylyl cyclase.

L.Ramos-Espiritu, S.Kleinboelting, F.A.Navarrete, A.Alvau, P.E.Visconti, F.Valsecchi, A.Starkov, G.Manfredi, H.Buck, C.Adura, J.H.Zippin, J.van den Heuvel, J.F.Glickman, C.Steegborn, L.R.Levin, J.Buck.

ABSTRACT

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.