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ChemMedChem
Volumn 2, Issue 6, 2007, Pages 815-826
Homology modeling of the serotonin transporter: Insights into the primary escitalopram-binding site
Author keywords

Escitalopram; Homology modeling; Molecular recognition; Serotonin transporter; Structure activity relationships
Indexed keywords

CITALOPRAM; ESCHERICHIA COLI PROTEIN; LEUCINE; LIGAND; SEROTONIN TRANSPORTER; SODIUM;
EID: 41149147416     PISSN: 18607179     EISSN: 18607187     Source Type: Journal    
DOI: 10.1002/cmdc.200600242     Document Type: Article
Times cited : (42)
References (76)
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    • At this modeling stage we also tried to build the hSERT model around escitalopram, using the MOE environment tool.[41] In addition, we also tried to use a hSERT template for homology modeling escitalopram used as a MOE environment, where residues within the ligand-binding site had been mutated to alanine or glycine. However, none of the obtained hSERT models was suitable for the escitalopram-binding site
    • [41] In addition, we also tried to use a hSERT template for homology modeling (escitalopram used as a MOE environment), where residues within the ligand-binding site had been mutated to alanine or glycine. However, none of the obtained hSERT models was suitable for the escitalopram-binding site.
  • 48
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    • A less comprehensive backbone modification attempt, where flexibility was allowed only in TM1 and TM6, revealed that to obtain sufficient movements of the TM1 and TM6 unwound regions, some flexibility in TM3 and TM8 was also required.
    • A less comprehensive backbone modification attempt, where flexibility was allowed only in TM1 and TM6, revealed that to obtain sufficient movements of the TM1 and TM6 unwound regions, some flexibility in TM3 and TM8 was also required.
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    • Such a nonideal topology/geometry is expected to be important for 1) providing room for a ligand, 2) offering multiple protein-ligand and protein-sodium ion interactions involving backbone and side-chain atoms, and 3 inducing required conformational changes during the transport cycle, 22
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    • Despite one or both of the anchoring points for the three contacts differing between the two transporters, a comparison of our putative model with the LeuT X-ray structure reveals that similar architectures are maintained. In fact, the TM1-6 and TM1-8 contacts stretch over the same number of covalent bonds (measured backbone-to-backbone) and provide similar interhelical distances measured as C-C distances
    • Despite one or both of the anchoring points for the three contacts differing between the two transporters, a comparison of our putative model with the LeuT X-ray structure reveals that similar architectures are maintained. In fact, the TM1-6 and TM1-8 contacts stretch over the same number of covalent bonds (measured backbone-to-backbone) and provide similar interhelical distances (measured as C-C distances).
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    • F586 is also located in the same part of the transporter as residues proven to be important for transporter dimerization.[76] As shown in Figure 7, it is not located directly on the putative dimerization surface, but it might play a role as a link between the dimerization surface and the primary ligand-binding site
    • [76] As shown in Figure 7, it is not located directly on the putative dimerization surface, but it might play a role as a link between the dimerization surface and the primary ligand-binding site.
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    • During the model building, we observed that Y175 can adopt two conformations -pointing inward towards the ligand-binding site or outwards. We selected the inward-pointing rotamer.
    • During the model building, we observed that Y175 can adopt two conformations -pointing inward towards the ligand-binding site or outwards. We selected the inward-pointing rotamer.
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* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.