Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The crystal structure of a pepsin from the gastric mucosa of Atlantic cod has been determined to 2.16 A resolution. Data were collected on orthorhombic crystals with cell dimensions a = 35.98, b = 75.40 and c = 108.10 A, on a FAST area-detector system. The phase problem was solved by the molecular-replacement method using porcine pepsin (PDB entry 5PEP) as a search model. The structure has been refined to a crystallographic R factor of 20.8% using all reflections between 8.0 and 2.16 A, without prior knowledge of the primary sequence. The resulting crystal structure is very similar to the porcine enzyme, consisting of two domains with predominantly beta-sheet structure in the same sequential positions as the enzyme from pig. In the course of the model building, 122 residues were substituted and two residues deleted from the starting model to give a polypeptide chain of 324 amino acids and a sequence identity of 57.7% with the pig pepsin. No carbohydrate residues were located. Sequence alignment with available aspartic proteinases, indicates that the fish enzyme seems to be more related to mammalian gastric pepsins than to the mammalian gastricsins and chymosins, lysosomal cathepsin D's and a pepsin from tuna fish. The amino-acid composition of the cod enzyme, however, is more in accordance with the cathepsin D's.
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PMID:Structure and proposed amino-acid sequence of a pepsin from atlantic cod (Gadus morhua). 976 15

Plasmepsins (Plm) II (EC number: 3.4.23.39) and IV (EC number: 3.4.23.B14) are aspartic proteases present in the food vacuole of the malaria parasite Plasmodium falciparum and are involved in host hemoglobin degradation. Based on our established efficient synthetic sequence, a series of inhibitors for Plm II and IV has been synthesized bearing a 2,3,4,7-tetrahydro-1H-azepine scaffold as the core structural element. During the computational design cycle, thorough investigations were carried out in order to find a reasonable theoretical binding mode for Plm II and IV. The conformation of Plm II in the crystal structure (PDB code: 1LF2) provides a good starting geometry for our virtual screening approach. In contrast, the only available co-crystal structure for Plm IV of P. falciparum (PDB code: 1LS5) appears inappropriate for inhibitor design. Therefore, a homology model was constructed based on the Plm II 1LF2 structure. A combinatorial docking run using FlexX(c) suggested compounds which, after synthesis, turned out to exhibit affinities in the sub-micromolar range. The observed structure-activity relationships of the synthesized compounds confirm the assumed binding mode for Plm II and IV. The best-binding inhibitors designed for Plm II and IV are devoid of any inhibitory potency against human cathepsin D (EC number: 3.4.23.5).
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PMID:Computer-aided design and synthesis of nonpeptidic plasmepsin II and IV inhibitors. 1875 22