Src family kinase Hck with bound inhibitor A-641359

Discovery of A-770041, a Src-Family Selective Orally Active Lck Inhibitor that Prevents Organ Allograft Rejection.

A-420983: A Potent, Orally Active Inhibitor of Lck with Efficacy in a Model of Transplant Rejection

SRC NUMBERING USED. ADD 20 TO THE RESIDUE NUMBERS IN THIS ENTRY TO OBTAIN ACTUAL HUMAN HCK RESIDUE NUMBERS. RESIDUE Y501 (HCK Y521) IS PHOSPHORYLATED

HAEMATOPOETIC CELL KINASE HCK, P59-HCK/P60-HCK HEMOPOIETIC CELL KINASE

INTENSITIES WERE CONVERTED TO STRUCTURE FACTORS USING CCP4 PROGRAM TRUNCATE.

CRYSTALLIZATION CONDITIONS: HCK (10 MG/ML IN 150 MM NACL, 20 MM TRIS.HCL PH 8.0) WAS MIXED WITH A-641359 [100 MM STOCK SOLUTION OF THE MALEIC ACID SALT IN DMSO) TO GIVE A FINAL A-641359 CONCENTRATION OF 1 MM. HCK/A-641359 WAS THEN MIXED WITH RESERVOIR SOLUTION (12% PEG 6000, 3% 1, 5-DIAMINOPENTANE, 20% GLYCEROL, 200 MM CA(OAC)2, 100 MM TRIS.HCL PH 8.0) AND EQUILBRATED AGAINST THE RESERVOIR SOLUTION BY VAPOR DIFFUSION (SITTING DROPS) AT 277 K.

CRYSTAL STRUCTURE OF HCK IN COMPLEX WITH A SRC FAMILY- SELECTIVE TYROSINE KINASE INHIBITOR

SRC FAMILY KINASE HCK WITH BOUND INHIBITOR A-420983

SRC FAMILY KINASE HCK WITH BOUND INHIBITOR A-770041

NMR ENSEMBLE OF THE UNCOMPLEXED HUMAN HCK SH2 DOMAIN, 20 STRUCTURES

HUMAN HCK SH3 DOMAIN, NMR, 25 STRUCTURES

HUMAN HCK SH3 DOMAIN, NMR, MINIMIZED AVERAGE STRUCTURE

ENGINEERED RESIDUE IN CHAIN A, GLN 502 TO GLU ENGINEERED RESIDUE IN CHAIN A, GLN 503 TO GLU ENGINEERED RESIDUE IN CHAIN A, GLN 504 TO ILE ENGINEERED RESIDUE IN CHAIN B, GLN 502 TO GLU ENGINEERED RESIDUE IN CHAIN B, GLN 503 TO GLU ENGINEERED RESIDUE IN CHAIN B, GLN 504 TO ILE
THE PROTEIN CRYSTALLIZED INCLUDED EIGHT NON-NATIVE N-TERMINAL RESIDUES: GLY-ALA-MET-GLY-SER-GLY-ILE-ARG. Q502E, Q503E, Q504I TRIPLE MUTANT TO INCREASE THE PHOSPHORYLATION OF Y501 (ALL SRC NUMBERING).

HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. THE ACTIVATION LOOP (RESIDUES A386-A398 AND B386-B398) IS DISORDERED IN BOTH HCK MOLECULES (CHAINS A AND B). HCK CHAIN A IS SLIGHTLY BETTER ORDERED THAN CHAIN B. SIMILARLY, THE LIGAND A1506 IS BETTER ORDERED THAN B1506. SEVEN N-TERMINAL RESIDUES (FROM THE EXPRESSION VECTOR, GLY-ALA -MET-GLY-SER-GLY-ILE) ARE DISORDERED IN BOTH CHAINS. RESIDUE ARG-59 IS NON-NATIVE (EXPRESSION VECTOR).

TYROSINE-PROTEIN KINASE HCK (E.C.2.7.1.112)

TRANSFERASE, ATP-BINDING, KINASE, LIPOPROTEIN, MYRISTATE, NUCLEOTIDE-BINDING, PALMITATE, SH2 DOMAIN, SH3 DOMAIN