PMID- 27766889
OWN - NLM
STAT- MEDLINE
DCOM- 20170221
LR  - 20211204
IS  - 1475-6374 (Electronic)
IS  - 1475-6366 (Print)
IS  - 1475-6366 (Linking)
VI  - 32
IP  - 1
DP  - 2017 Dec
TI  - Discovery of Klotho peptide antagonists against Wnt3 and Wnt3a target proteins 
      using combination of protein engineering, protein-protein docking, peptide 
      docking and molecular dynamics simulations.
PG  - 84-98
LID - 10.1080/14756366.2016.1235569 [doi]
AB  - The Klotho is known as lifespan enhancing protein involved in antagonizing the 
      effect of Wnt proteins. Wnt proteins are stem cell regulators, and uninterrupted 
      exposure of Wnt proteins to the cell can cause stem and progenitor cell 
      senescence, which may lead to aging. Keeping in mind the importance of Klotho in 
      Wnt signaling, in silico approaches have been applied to study the important 
      interactions between Klotho and Wnt3 and Wnt3a (wingless-type mouse mammary tumor 
      virus (MMTV) integration site family members 3 and 3a). The main aim of the study 
      is to identify important residues of the Klotho that help in designing peptides 
      which can act as Wnt antagonists. For this aim, a protein engineering study is 
      performed for Klotho, Wnt3 and Wnt3a. During the theoretical analysis of homology 
      models, unexpected role of number of disulfide bonds and secondary structure 
      elements has been witnessed in case of Wnt3 and Wnt3a proteins. Different in 
      silico experiments were carried out to observe the effect of correct number of 
      disulfide bonds on 3D protein models. For this aim, total of 10 molecular 
      dynamics (MD) simulations were carried out for each system. Based on the 
      protein-protein docking simulations of selected protein models of Klotho with 
      Wnt3 and Wnt3a, different peptides derived from Klotho have been designed. Wnt3 
      and Wnt3a proteins have three important domains: Index finger, N-terminal domain 
      and a patch of  approximately 10 residues on the solvent exposed surface of palm domain. 
      Protein-peptide docking of designed peptides of Klotho against three important 
      domains of palmitoylated Wnt3 and Wnt3a yields encouraging results and leads 
      better understanding of the Wnt protein inhibition by proposed Klotho peptides. 
      Further in vitro studies can be carried out to verify effects of novel designed 
      peptides as Wnt antagonists.
FAU - Mirza, Shaher Bano
AU  - Mirza SB
AD  - a Department of Biophysics, School of Medicine , Bahcesehir University (BAU) , 
      Istanbul , Turkey.
AD  - b Department of Biosciences , COMSATS Institute of Information Technology (CIIT) 
      , Islamabad , Pakistan.
FAU - Ekhteiari Salmas, Ramin
AU  - Ekhteiari Salmas R
AD  - a Department of Biophysics, School of Medicine , Bahcesehir University (BAU) , 
      Istanbul , Turkey.
FAU - Fatmi, M Qaiser
AU  - Fatmi MQ
AD  - b Department of Biosciences , COMSATS Institute of Information Technology (CIIT) 
      , Islamabad , Pakistan.
FAU - Durdagi, Serdar
AU  - Durdagi S
AD  - a Department of Biophysics, School of Medicine , Bahcesehir University (BAU) , 
      Istanbul , Turkey.
LA  - eng
PT  - Journal Article
DEP - 20161021
PL  - England
TA  - J Enzyme Inhib Med Chem
JT  - Journal of enzyme inhibition and medicinal chemistry
JID - 101150203
RN  - 0 (Peptides)
RN  - 0 (WNT3 protein, human)
RN  - 0 (Wnt3 Protein)
RN  - EC 3.2.1.31 (Glucuronidase)
RN  - EC 3.2.1.31 (Klotho Proteins)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Glucuronidase/*chemistry
MH  - Humans
MH  - Klotho Proteins
MH  - Mice
MH  - Molecular Dynamics Simulation
MH  - Peptides/chemistry/*pharmacology
MH  - *Protein Engineering
MH  - Wnt3 Protein/*antagonists & inhibitors
PMC - PMC6009926
OTO - NOTNLM
OT  - Homology modeling
OT  - Klotho
OT  - Wnt3
OT  - Wnt3a
OT  - molecular dynamics (MD) simulations
OT  - peptide design
OT  - protein engineering
OT  - protein-protein docking
EDAT- 2016/10/22 06:00
MHDA- 2017/02/22 06:00
PMCR- 2016/10/21
CRDT- 2016/10/22 06:00
PHST- 2016/10/22 06:00 [pubmed]
PHST- 2017/02/22 06:00 [medline]
PHST- 2016/10/22 06:00 [entrez]
PHST- 2016/10/21 00:00 [pmc-release]
AID - 1235569 [pii]
AID - 10.1080/14756366.2016.1235569 [doi]
PST - ppublish
SO  - J Enzyme Inhib Med Chem. 2017 Dec;32(1):84-98. doi: 
      10.1080/14756366.2016.1235569. Epub 2016 Oct 21.