PDBsum entry 4zj5

Hydrolase/hydrolase inhibitor

PDB id: 4zj5

Contents

Protein chain

239 a.a.

Ligands

CYS-PRO-LYS-ARG-PHE-ALA-ALA-LEU-PHE-CYS

SO4 ×4

MRZ

Waters ×107

Obsolete entry

PDB id:

4zj5

Name:

Hydrolase/hydrolase inhibitor

Title:

The crystal structure of human plasma kallikrein in complex with its peptide inhibitor pkalin-2

Structure:

Plasma kallikrein light chain. Chain: a. Fragment: unp residues 391-629. Synonym: fletcher factor,kininogenin,plasma prekallikrein. Engineered: yes. Mutation: yes. Cys-pro-lys-arg-phe-m70-ala-leu-phe-cys. Chain: p. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: klkb1, klk3. Expressed in: komagataella pastoris. Expression_system_taxid: 4922. Synthetic: yes. Synthetic construct. Organism_taxid: 32630

Resolution:

1.75Å R-factor: 0.231 R-free: 0.245

Authors:

M.Xu,L.Jiang,P.Xu,Z.Luo,P.Andreasen,M.Huang

Key ref:

P.Xu et al. (2015). Design of Specific Serine Protease Inhibitors Based on a Versatile Peptide Scaffold: Conversion of a Urokinase Inhibitor to a Plasma Kallikrein Inhibitor. J Med Chem, 58, 8868-8876. PubMed id: 26536069 DOI: 10.1021/acs.jmedchem.5b01128

Date:

29-Apr-15 Release date: 18-Nov-15

Protein chain

P03952  (KLKB1_HUMAN) -  Plasma kallikrein from Homo sapiens

Seq: 638 a.a.

Struc: 239 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.4.21.34 - plasma kallikrein.
• Reaction: Cleaves selectively Arg-|-Xaa and Lys-|-Xaa bonds, including Lys-|-Arg and Arg-|-Ser bonds in (human) kininogen to release bradykinin.

DOI no: 10.1021/acs.jmedchem.5b01128

J Med Chem 58:8868-8876 (2015)

PubMed id: 26536069

Design of Specific Serine Protease Inhibitors Based on a Versatile Peptide Scaffold: Conversion of a Urokinase Inhibitor to a Plasma Kallikrein Inhibitor.

P.Xu, M.Xu, L.Jiang, Q.Yang, Z.Luo, Z.Dauter, M.Huang, P.A.Andreasen.

ABSTRACT

All serine proteases hydrolyze peptide bonds by the same basic mechanism and have very similar active sites, in spite of the fact that individual proteases have different physiological functions. We here report a strategy for designing high-affinity and high-specificity serine protease inhibitors using a versatile peptide scaffold, a 10-mer peptide, mupain-1 (CPAYSRYLDC). Mupain-1 was previously reported as a specific inhibitor of murine urokinase-type plasminogen activator (Ki = 0.55 μM) without measurable affinity to plasma kallikrein (Ki > 1000 μM). On the basis of a structure-based rational design, we substituted five residues of mupain-1 and converted it to a potent plasma kallikrein inhibitor (Ki = 0.014 μM). X-ray crystal structure analysis showed that the new peptide was able to adapt a new set of enzyme surface interactions by a slightly changed backbone conformation. Thus, with an appropriate re-engineering, mupain-1 can be redesigned to specific inhibitors of other serine proteases.