The Crystal Structure of the Plasmodium falciparum PdxK Provides an Experimental Model for Pro-Drug Activation

Autor(es)

Gao, Kai ^[1] ; Wang, Wenjia ^[1] ; Kronenberger, Thales ^{[2, 3]} ; Wrenger, Carsten ^[2] ; Groves, Matthew R. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Groningen, Groningen Res Inst Pharm, Drug Design XB20, NL-9700 AD Groningen - Netherlands

^[2] Univ Sao Paulo, Inst Biomed Sci, Dept Parasitol, Unit Drug Discovery, BR-05508000 Sao Paulo, SP - Brazil

^[3] Univ Hosp Tubingen, Dept Med Oncol & Pneumol, Internal Med 8, D-72076 Tubingen - Germany

• Tipo de documento: Artigo Científico
• Fonte: CRYSTALS; v. 9, n. 10 OCT 2019.
• Citações Web of Science: 0

Resumo

Pyridoxine/pyridoxal kinase (PdxK), belongs to the ribokinase family and is involved in the vitamin B6 salvage pathway by phosphorylating 5-pyridoxal (PL) into an active form. In the human malaria parasite, Plasmodium falciparum, PfPdxK functions to salvage vitamin B6 from both itself and its host. Here, we report the crystal structure of PfPdxK from P. falciparum in complex with a non-hydrolyzable ATP analog (AMP-PNP) and PL. As expected, the fold is retained and both AMP-PNP and PL occupy the same binding sites when compared to the human ortholog. However, our model allows us to identify a FIxxIIxL motif at the C terminus of the disordered repeat motif (XNXH)(m) that is implicated in binding the WD40 domain and may provide temporal control of PfPdxK through an interaction with a E3 ligase complex. Furthermore, molecular docking approaches based on our model allow us to explain differential PfPdxK phosphorylation and activation of a novel class of potent antimalarials (PT3, PT5 and PHME), providing a basis for further development of these compounds. Finally, the structure of PfPdxK provides a high-quality model for a better understanding of vitamin B6 synthesis and salvage in the parasite. (AU)

• Processo FAPESP: 17/03966-4 - Alvejando a via de recuperação e biossíntese de ácido lipoico em MRSA
• Beneficiário: Carsten Wrenger
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 14/03644-9 - Sítios de interação alternativos em receptores nucleares e sua viabilidade como alvos terapêuticos usando triagem computacional e experimental
• Beneficiário: Thales Kronenberger
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 15/26722-8 - Drug discovery contra doenças infecciosas humanos
• Beneficiário: Carsten Wrenger
• Modalidade de apoio: Auxílio à Pesquisa - Temático