PDBsum entry 4z3v

Transferase

PDB id

4z3v

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Contents

			Protein chain

					271 a.a.

			Ligands

					IMD ×2


					IPA


					EDO


					4L6

			Waters ×406

PDB id:

4z3v

Links

Name:

Transferase

Title:

Fragment-based discovery of a small molecule reversible inhibitor of bruton's tyrosine kinase

Structure:

Tyrosine-protein kinase btk. Chain: a. Fragment: unp residues 416-693. Synonym: agammaglobulinemia tyrosine kinase,atk,b-cell progenitor kinase,bpk,bruton tyrosine kinase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: btk, agmx1, atk, bpk. Expressed in: unidentified baculovirus. Expression_system_taxid: 10469.

Resolution:

1.60Å

R-factor:

0.166

R-free:

0.198

Authors:

D.R.Dougan

Key ref:

C.R.Smith et al. (2015). Fragment-Based Discovery of a Small Molecule Inhibitor of Bruton's Tyrosine Kinase. J Med Chem, 58, 5437-5444. PubMed id: 26087137 DOI: 10.1021/acs.jmedchem.5b00734

Date:

31-Mar-15

Release date:

01-Jul-15

PROCHECK

	Headers

	References

Protein chain

Q06187 (BTK_HUMAN) - Tyrosine-protein kinase BTK from Homo sapiens

Seq: Struc:

Seq: Struc:					659 a.a. 271 a.a.

Key:

PfamA domain

Secondary structure

CATH domain



		Enzyme reactions

Enzyme class:

E.C.2.7.10.2 - non-specific protein-tyrosine kinase.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

Reaction:

L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

L-tyrosyl-[protein]	+	ATP	=	O-phospho-L-tyrosyl-[protein]	+	ADP	+	H(+)

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

Added reference

DOI no: 10.1021/acs.jmedchem.5b00734	J Med Chem 58:5437-5444 (2015)
PubMed id: 26087137

Fragment-Based Discovery of a Small Molecule Inhibitor of Bruton's Tyrosine Kinase.
C.R.Smith, D.R.Dougan, M.Komandla, T.Kanouni, B.Knight, J.D.Lawson, M.Sabat, E.R.Taylor, P.Vu, C.Wyrick.

ABSTRACT

The discovery and optimization of a series of 4-aminocinnoline-3-carboxamide inhibitors of Bruton's tyrosine kinase are reported. A fragment-based screening approach incorporating X-ray co-crystallography was used to identify a cinnoline fragment and characterize its binding mode in the ATP binding site of Btk. Optimization of the fragment hit resulted in the identification of a lead compound which reduced paw swelling in a dose- and exposure-dependent fashion in a rat model of collagen-induced arthritis.