PDBsum entry 4oz2

Lyase

PDB id: 4oz2

Contents

Protein chain

469 a.a.

Ligands

1Z6

GOL ×3

Metals

_CL

Waters ×474

PDB id:

4oz2

Name:

Lyase

Title:

Human solac complexed with 4-(4-fluorophenyl)-3-methyl-1h-pyrazole

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

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: adcy10, sac. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

2.10Å R-factor: 0.169 R-free: 0.222

Authors:

M.Vinkovic

Key ref:

S.M.Saalau-Bethell et al. (2014). Crystal structure of human soluble adenylate cyclase reveals a distinct, highly flexible allosteric bicarbonate binding pocket. Chemmedchem, 9, 823-832. PubMed id: 24616449 DOI: 10.1002/cmdc.201300480

Date:

13-Feb-14 Release date: 02-Apr-14

Protein chain

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

Seq: 1610 a.a.

Struc: 468 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
• Cofactor: Pyridoxal 5'-phosphate

Pyridoxal 5'-phosphate (Bound ligand (Het Group name = 1Z6) matches with 45.00% similarity)

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

reference

DOI no: 10.1002/cmdc.201300480

Chemmedchem 9:823-832 (2014)

PubMed id: 24616449

Crystal structure of human soluble adenylate cyclase reveals a distinct, highly flexible allosteric bicarbonate binding pocket.

S.M.Saalau-Bethell, V.Berdini, A.Cleasby, M.Congreve, J.E.Coyle, V.Lock, C.W.Murray, M.A.O'Brien, S.J.Rich, T.Sambrook, M.Vinkovic, J.R.Yon, H.Jhoti.

ABSTRACT

Soluble adenylate cyclases catalyse the synthesis of the second messenger cAMP through the cyclisation of ATP and are the only known enzymes to be directly activated by bicarbonate. Here, we report the first crystal structure of the human enzyme that reveals a pseudosymmetrical arrangement of two catalytic domains to produce a single competent active site and a novel discrete bicarbonate binding pocket. Crystal structures of the apo protein, the protein in complex with α,β-methylene adenosine 5'-triphosphate (AMPCPP) and calcium, with the allosteric activator bicarbonate, and also with a number of inhibitors identified using fragment screening, all show a flexible active site that undergoes significant conformational changes on binding of ligands. The resulting nanomolar-potent inhibitors that were developed bind at both the substrate binding pocket and the allosteric site, and can be used as chemical probes to further elucidate the function of this protein.