3MA2

Complex membrane type-1 matrix metalloproteinase (MT1-MMP) with tissue inhibitor of metalloproteinase-1 (TIMP-1)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.05 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.199 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

The Intrinsic Protein Flexibility of Endogenous Protease Inhibitor TIMP-1 Controls Its Binding Interface and Affects Its Function.

Grossman, M.Tworowski, D.Dym, O.Lee, M.H.Levy, Y.Murphy, G.Sagi, I.

(2010) Biochemistry 49: 6184-6192

  • DOI: https://doi.org/10.1021/bi902141x
  • Primary Citation of Related Structures:  
    3MA2

  • PubMed Abstract: 

    Protein flexibility is thought to play key roles in numerous biological processes, including antibody affinity maturation, signal transduction, and enzyme catalysis, yet only limited information is available regarding the molecular details linking protein dynamics with function. A single point mutation at the distal site of the endogenous tissue inhibitor of metalloproteinase 1 (TIMP-1) enables this clinical target protein to tightly bind and inhibit membrane type 1 matrix metalloproteinase (MT1-MMP) by increasing only the association constant. The high-resolution X-ray structure of this complex determined at 2 A could not explain the mechanism of enhanced binding and pointed to a role for protein conformational dynamics. Molecular dynamics (MD) simulations reveal that the high-affinity TIMP-1 mutants exhibit significantly reduced binding interface flexibility and more stable hydrogen bond networks. This was accompanied by a redistribution of the ensemble of substrates to favorable binding conformations that fit the enzyme catalytic site. Apparently, the decrease in backbone flexibility led to a lower entropy cost upon formation of the complex. This work quantifies the effect of a single point mutation on the protein conformational dynamics and function of TIMP-1. Here we argue that controlling the intrinsic protein dynamics of MMP endogenous inhibitors may be utilized for rationalizing the design of selective novel protein inhibitors for this class of enzymes.


  • Organizational Affiliation

    Department of Structural Biology, Weizmann Institute of Science, Rehovot, Israel.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Matrix metalloproteinase-14A [auth D],
B [auth A]
181Homo sapiensMutation(s): 0 
Gene Names: MMP14
EC: 3.4.24.80
UniProt & NIH Common Fund Data Resources
Find proteins for P50281 (Homo sapiens)
Explore P50281 
Go to UniProtKB:  P50281
PHAROS:  P50281
GTEx:  ENSG00000157227 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP50281
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Metalloproteinase inhibitor 1C [auth B],
D [auth C]
125Homo sapiensMutation(s): 3 
Gene Names: TIMP1CLGITIMP
UniProt & NIH Common Fund Data Resources
Find proteins for P01033 (Homo sapiens)
Explore P01033 
Go to UniProtKB:  P01033
PHAROS:  P01033
GTEx:  ENSG00000102265 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP01033
Sequence Annotations
Expand
  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.05 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.199 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 59.69α = 90
b = 63.649β = 105.86
c = 87.158γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
PHASERphasing
REFMACrefinement
HKL-2000data reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-06-30
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2015-01-28
    Changes: Structure summary
  • Version 1.3: 2021-10-06
    Changes: Database references, Derived calculations
  • Version 1.4: 2023-09-06
    Changes: Data collection, Refinement description