5H0B
Crystal structure of HCK complexed with a pyrrolo-pyrimidine inhibitor (S)-2-(((1r,4S)-4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)amino)-4-methylpentanoic acid
Summary for 5H0B
| Entry DOI | 10.2210/pdb5h0b/pdb |
| Related | 5H09 5H0A 5H0C 5H0D 5H0E 5H0F 5H0G 5H0H |
| Descriptor | Tyrosine-protein kinase HCK, (2~{S})-2-[[4-[4-azanyl-5-(4-phenoxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl]azaniumyl]-4-methyl-pentanoate (3 entities in total) |
| Functional Keywords | transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (Human) |
| Cellular location | Isoform 1: Lysosome. Isoform 2: Cell membrane ; Lipid-anchor . Cytoplasmic vesicle, secretory vesicle: P08631 |
| Total number of polymer chains | 1 |
| Total formula weight | 52513.86 |
| Authors | Tomabechi, Y.,Kukimoto-Niino, M.,Shirouzu, M. (deposition date: 2016-10-04, release date: 2017-10-11, Last modification date: 2024-10-30) |
| Primary citation | Yuki, H.,Kikuzato, K.,Koda, Y.,Mikuni, J.,Tomabechi, Y.,Kukimoto-Niino, M.,Tanaka, A.,Shirai, F.,Shirouzu, M.,Koyama, H.,Honma, T. Activity cliff for 7-substituted pyrrolo-pyrimidine inhibitors of HCK explained in terms of predicted basicity of the amine nitrogen. Bioorg. Med. Chem., 25:4259-4264, 2017 Cited by PubMed Abstract: We previously reported the structure-based design of a highly potent hematopoietic cell kinase (HCK) inhibitor, a pyrrolo-pyrimidine compound designated RK-20449, for treatment of recurrent leukemia. Herein we report the synthesis and structure-activity relationships of some amino acid derivatives of 7-substituted pyrrolo-pyrimidine. Although these derivatives had the same predicted binding conformation as RK-20449, their IC values were 100-1000 times larger than that of the parent compound. We assumed that the basicity of the amine nitrogen, which formed an ionic bond with Asp348 of HCK, markedly affected inhibitory activity against HCK. The pKa values of the nitrogen were predicted by means of an ab initio quantum mechanical method, and complexes of the derivatives with HCK were analyzed by X-ray crystallography. We observed a significant correlation between the predicted pKa and IC values, and the crystal structures of the less potent derivatives showed various types of defects around the ionic bond. PubMed: 28662963DOI: 10.1016/j.bmc.2017.05.053 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.651 Å) |
Structure validation
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