5BV7

Crystal structure of human LCAT (L4F, N5D) in complex with Fab of an agonistic antibody


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.45 ?
  • R-Value Free: 
    0.241 (Depositor), 0.240 (DCC) 
  • R-Value Work: 
    0.189 (Depositor), 0.190 (DCC) 
  • R-Value Observed: 
    0.191 (Depositor) 

Starting Model: experimental
View more details

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 2.2 of the entry. See complete history


Literature

Agonistic Human Antibodies Binding to Lecithin-Cholesterol Acyltransferase Modulate High Density Lipoprotein Metabolism.

Gunawardane, R.N.Fordstrom, P.Piper, D.E.Masterman, S.Siu, S.Liu, D.Brown, M.Lu, M.Tang, J.Zhang, R.Cheng, J.Gates, A.Meininger, D.Chan, J.Carlson, T.Walker, N.Schwarz, M.Delaney, J.Zhou, M.

(2016) J Biological Chem 291: 2799-2811

  • DOI: https://doi.org/10.1074/jbc.M115.672790
  • Primary Citation of Related Structures:  
    5BV7

  • PubMed Abstract: 

    Drug discovery opportunities where loss-of-function alleles of a target gene link to a disease-relevant phenotype often require an agonism approach to up-regulate or re-establish the activity of the target gene. Antibody therapy is increasingly recognized as a favored drug modality due to multiple desirable pharmacological properties. However, agonistic antibodies that enhance the activities of the target enzymes are rarely developed because the discovery of agonistic antibodies remains elusive. Here we report an innovative scheme of discovery and characterization of human antibodies capable of binding to and agonizing a circulating enzyme lecithin cholesterol acyltransferase (LCAT). Utilizing a modified human LCAT protein with enhanced enzymatic activity as an immunogen, we generated fully human monoclonal antibodies using the XenoMouse(TM) platform. One of the resultant agonistic antibodies, 27C3, binds to and substantially enhances the activity of LCAT from humans and cynomolgus macaques. X-ray crystallographic analysis of the 2.45 ? LCAT-27C3 complex shows that 27C3 binding does not induce notable structural changes in LCAT. A single administration of 27C3 to cynomolgus monkeys led to a rapid increase of plasma LCAT enzymatic activity and a 35% increase of the high density lipoprotein cholesterol that was observed up to 32 days after 27C3 administration. Thus, this novel scheme of immunization in conjunction with high throughput screening may represent an effective strategy for discovering agonistic antibodies against other enzyme targets. 27C3 and other agonistic human anti-human LCAT monoclonal antibodies described herein hold potential for therapeutic development for the treatment of dyslipidemia and cardiovascular disease.


  • Organizational Affiliation

    From Therapeutic Discovery, Amgen Inc., Seattle, Washington 98119.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Phosphatidylcholine-sterol acyltransferase422Homo sapiensMutation(s): 2 
EC: 2.3.1.43 (PDB Primary Data), 3.1.1.47 (UniProt)
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for P04180 (Homo sapiens)
Explore P04180 
Go to UniProtKB:  P04180
PHAROS:  P04180
GTEx:  ENSG00000213398 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP04180
Glycosylation
Glycosylation Sites: 3Go to GlyGen: P04180-1
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
27C3 light chainB [auth L]214Homo sapiensMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
27C3 heavy chainC [auth H]233Homo sapiensMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
Fab1 light chainD [auth B]213Homo sapiensMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 5
MoleculeChains Sequence LengthOrganismDetailsImage
Fab1 heavy chainE [auth C]238Homo sapiensMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
Expand
  • Reference Sequence
Oligosaccharides

Help

Entity ID: 6
MoleculeChains Length2D Diagram Glycosylation3D Interactions
alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]alpha-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-3)]alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranoseF [auth D]7N-Glycosylation
Glycosylation Resources
GlyTouCan:  G09609EN
GlyCosmos:  G09609EN
GlyGen:  G09609EN
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.45 ?
  • R-Value Free:  0.241 (Depositor), 0.240 (DCC) 
  • R-Value Work:  0.189 (Depositor), 0.190 (DCC) 
  • R-Value Observed: 0.191 (Depositor) 
Space Group: P 21 21 21
Unit Cell:
Length ( ? )Angle ( ? )
a = 57.944¦Á = 90
b = 127.595¦Â = 90
c = 256.079¦Ă = 90
Software Package:
Software NamePurpose
Aimlessdata scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
PHASERphasing
MOSFLMdata reduction
Aimlessdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-12-16
    Type: Initial release
  • Version 1.1: 2015-12-23
    Changes: Data collection, Database references
  • Version 1.2: 2016-02-17
    Changes: Database references
  • Version 1.3: 2018-08-22
    Changes: Data collection, Database references, Derived calculations, Source and taxonomy, Structure summary
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Derived calculations, Structure summary
  • Version 2.1: 2023-09-27
    Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary
  • Version 2.2: 2024-10-30
    Changes: Structure summary
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