PDBsum entry 7agd

Antibiotic

PDB id: 7agd

Contents

Protein chains

339 a.a.

Ligands

BOC-VAL-VAL-PSA-ALA-PSA ×4

1PE ×2

PEG

PGE ×3

MES

FOR

Metals

_NA

Waters ×782

PDB id:

7agd

Name:

Antibiotic

Title:

Protease sapp1p from candida parapsilosis in complex with kb75

Structure:

Candidapepsin. Chain: a, b, c, d. Engineered: yes. Kb75. Chain: i, j, k, l. Engineered: yes

Source:

Candida parapsilosis. Yeast. Organism_taxid: 5480. Gene: sapp1. Expressed in: candida parapsilosis. Expression_system_taxid: 5480. Synthetic: yes. Streptomyces albus. Organism_taxid: 1888

Resolution:

1.80Å R-factor: 0.202 R-free: 0.223

Authors:

J.Dostal,O.Heidingsfeld,J.Brynda

Key ref:

J.Dostál et al. (2021). Structural determinants for subnanomolar inhibition of the secreted aspartic protease Sapp1p from Candida parapsilosis. J Enzyme Inhib Med Chem, 36, 914-921. PubMed id: 33843395 DOI: 10.1080/14756366.2021.1906664

Date:

22-Sep-20 Release date: 21-Apr-21

Protein chains

P32951  (CARP1_CANPA) -  Candidapepsin-1 from Candida parapsilosis

Seq: 402 a.a.

Struc: 339 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.3.4.23.24 - candidapepsin.
• Reaction: Preferential cleavage at the carboxyl of hydrophobic amino acids, but fails to cleave 15-Leu-|-Tyr-16, 16-Tyr-|-Leu-17 and 24-Phe-|-Phe-25 of insulin B chain. Activates trypsinogen, and degrades keratin.

DOI no: 10.1080/14756366.2021.1906664

J Enzyme Inhib Med Chem 36:914-921 (2021)

PubMed id: 33843395

Structural determinants for subnanomolar inhibition of the secreted aspartic protease Sapp1p from Candida parapsilosis.

J.Dostál, J.Brynda, L.Vaňková, S.R.Zia, I.Pichová, O.Heidingsfeld, M.Lepšík.

ABSTRACT

Pathogenic Candida albicans yeasts frequently cause infections in hospitals. Antifungal drugs lose effectiveness due to other Candida species and resistance. New medications are thus required. Secreted aspartic protease of C. parapsilosis (Sapp1p) is a promising target. We have thus solved the crystal structures of Sapp1p complexed to four peptidomimetic inhibitors. Three potent inhibitors (K_i: 0.1, 0.4, 6.6 nM) resembled pepstatin A (K_i: 0.3 nM), a general aspartic protease inhibitor, in terms of their interactions with Sapp1p. However, the weaker inhibitor (K_i: 14.6 nM) formed fewer nonpolar contacts with Sapp1p, similarly to the smaller HIV protease inhibitor ritonavir (K_i: 1.9 µM), which, moreover, formed fewer H-bonds. The analyses have revealed the structural determinants of the subnanomolar inhibition of C. parapsilosis aspartic protease. Because of the high similarity between Saps from different Candida species, these results can further be used for the design of potent and specific Sap inhibitor-based antimycotic drugs.