Combined Computational and Structural Approach into Understanding the Role of Peptide Binding and Activation of Melanocortin Receptor 4

Zachmann, Julian; Kritsi, Eftichia; Tapeinou, Anthi; Zoumpoulakis, Panagiotis; Tselios, Theodore; Matsoukas, Minos‐Timotheos

doi:10.1021/acs.jcim.9b01196

Cited by 4 publications

(4 citation statements)

References 42 publications

(77 reference statements)

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“…The molecular framework gene SORCS1 encodes a membrane protein that is highly expressed in neurons and is involved in downregulating the expression of agouti-related peptide (AGRP) [ 58 , 59 ]. AGRP has been linked to MS and is a secreted molecule that binds to and is an antagonist of the melanocortin-4 receptor (MC4R) [ 60 , 61 , 62 ]. MC4Rs are highly expressed in ODCs and their precursor cells.…”

Section: Discussionmentioning

confidence: 99%

Whole Exome Sequencing in Multi-Incident Families Identifies Novel Candidate Genes for Multiple Sclerosis

Horjus

Mourik-Banda

Heerings

et al. 2022

IJMS

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Multiple sclerosis (MS) is a degenerative disease of the central nervous system in which auto-immunity-induced demyelination occurs. MS is thought to be caused by a complex interplay of environmental and genetic risk factors. While most genetic studies have focused on identifying common genetic variants for MS through genome-wide association studies, the objective of the present study was to identify rare genetic variants contributing to MS susceptibility. We used whole exome sequencing (WES) followed by co-segregation analyses in nine multi-incident families with two to four affected individuals. WES was performed in 31 family members with and without MS. After applying a suite of selection criteria, co-segregation analyses for a number of rare variants selected from the WES results were performed, adding 24 family members. This approach resulted in 12 exonic rare variants that showed acceptable co-segregation with MS within the nine families, implicating the genes MBP, PLK1, MECP2, MTMR7, TOX3, CPT1A, SORCS1, TRIM66, ITPR3, TTC28, CACNA1F, and PRAM1. Of these, three genes (MBP, MECP2, and CPT1A) have been previously reported as carrying MS-related rare variants. Six additional genes (MTMR7, TOX3, SORCS1, ITPR3, TTC28, and PRAM1) have also been implicated in MS through common genetic variants. The proteins encoded by all twelve genes containing rare variants interact in a molecular framework that points to biological processes involved in (de-/re-)myelination and auto-immunity. Our approach provides clues to possible molecular mechanisms underlying MS that should be studied further in cellular and/or animal models.

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Section: Discussionmentioning

confidence: 99%

Whole Exome Sequencing in Multi-Incident Families Identifies Novel Candidate Genes for Multiple Sclerosis

Horjus

Mourik-Banda

Heerings

et al. 2022

IJMS

View full text Add to dashboard Cite

show abstract

“…The molecular framework gene SORCS1 encodes a membrane protein that is highly expressed in neurons and is involved in downregulating the expression of agouti-related peptide (AGRP) 63,64 . AGRP has been linked to MS and is a secreted molecule that binds to and is an antagonist of the melanocortin-4 receptor (MC4R) [65][66][67] . MC4Rs are highly expressed in ODCs and their precursor cells.…”

Section: Discussionmentioning

confidence: 99%

Whole exome sequencing in multi-incident families identifies novel candidate genes for multiple sclerosis

Horjus

Banda

Heerings

et al. 2022

Preprint

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Multiple sclerosis (MS) is a degenerative disease of the central nervous system in which auto-immunity-induced demyelination occurs. MS is thought to be caused by a complex interplay of environmental and genetic risk factors. While most genetic studies have focused on identifying common genetic variants for MS through genome-wide association studies, the objective of the present study was to identify rare genetic variants contributing to MS susceptibility. We used whole exome sequencing (WES) followed by co-segregation analyses in nine multi-incident families with 2 to 4 affected individuals. WES was performed in 31 family members with and without MS. After applying a suite of selection criteria, co-segregation analyses for a number of rare variants selected from the WES results were performed, adding 24 family members. This approach resulted in 12 exonic rare variants that showed acceptable co-segregation with MS within the nine families, implicating the genes MBP, PLK1, MECP2, MTMR7, TOX3, CPT1A, SORCS1, TRIM66, ITPR3, TTC28, CACNA1F, and PRAM1. Of these, three genes (MBP, MECP2, and CPT1A) have been previously reported as carrying MS-related rare variants. Six additional genes (MTMR7, TOX3, SORCS1, ITPR3, TTC28, and PRAM1) have also been implicated in MS through common genetic variants. The proteins encoded by all twelve genes containing rare variants interact in a molecular framework that points to biological processes involved in (de-/re-)myelination and auto-immunity. Our approach provides clues to possible molecular mechanisms underlying MS that should be further studied in cellular and/or animal models.

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“…Docking of larger peptides requires tools dedicated to flexible peptide docking, protein–protein docking or modeling protocols tailored to particular GPCR–peptide systems. The examples include template-based modeling using Rosetta [ 12 ], manual docking guided by nuclear magnetic resonance data [ 13 ], CABS-dock docking followed by selection of plausible models [ 14 ], application of the hybrid molecular modeling protocol that integrates heterogeneous experimental data with force field-based calculations [ 15 ], application of ZDOCK and RDOCK tools for protein–protein docking [ 16 ] and GalaxyPepDock [ 17 ]. Nevertheless, the performance of neither of these methods was evaluated by prediction of a larger set of different GPCR–peptide complexes.…”

Section: Introductionmentioning

confidence: 99%

Docking of peptides to GPCRs using a combination of CABS-dock with FlexPepDock refinement

Badaczewska-Dawid¹,

Kmiecik²,

Koliński³

2020

Briefings in Bioinformatics

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The structural description of peptide ligands bound to G protein-coupled receptors (GPCRs) is important for the discovery of new drugs and deeper understanding of the molecular mechanisms of life. Here we describe a three-stage protocol for the molecular docking of peptides to GPCRs using a set of different programs: (1) CABS-dock for docking fully flexible peptides; (2) PD2 method for the reconstruction of atomistic structures from C-alpha traces provided by CABS-dock and (3) Rosetta FlexPepDock for the refinement of protein–peptide complex structures and model scoring. We evaluated the proposed protocol on the set of seven different GPCR–peptide complexes (including one containing a cyclic peptide), for which crystallographic structures are available. We show that CABS-dock produces high resolution models in the sets of top-scored models. These sets of models, after reconstruction to all-atom representation, can be further improved by Rosetta high-resolution refinement and/or minimization, leading in most of the cases to sub-Angstrom accuracy in terms of interface root-mean-square-deviation measure.

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Combined Computational and Structural Approach into Understanding the Role of Peptide Binding and Activation of Melanocortin Receptor 4

Cited by 4 publications

References 42 publications

Whole Exome Sequencing in Multi-Incident Families Identifies Novel Candidate Genes for Multiple Sclerosis

Whole Exome Sequencing in Multi-Incident Families Identifies Novel Candidate Genes for Multiple Sclerosis

Whole exome sequencing in multi-incident families identifies novel candidate genes for multiple sclerosis

Docking of peptides to GPCRs using a combination of CABS-dock with FlexPepDock refinement

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